Background Dissemination of clinical guidelines is necessary but seldom sufficient by itself to ensure the reliable uptake of evidence-based practice. There are further challenges in implementing multiple clinical guidelines and clinical practice recommendations in the pressurised environment of general practice. Objectives We aimed to develop and evaluate an implementation package that could be adapted to support the uptake of a range of clinical guideline recommendations and be sustainably integrated within general practice systems and resources. Over five linked work packages, we developed ‘high-impact’ quality indicators to show where a measurable change in clinical practice can improve patient outcomes (work package 1), analysed adherence to selected indicators (work package 2), developed an adaptable implementation package (work package 3), evaluated the effects and cost-effectiveness of adapted implementation packages targeting four indicators (work package 4) and examined intervention fidelity and mechanisms of action (work package 5). Setting and participants Health-care professionals and patients from general practices in West Yorkshire, UK. Design We reviewed recommendations from existing National Institute for Health and Care Excellence clinical guidance and used a multistage consensus process, including 11 professionals and patients, to derive a set of ‘high-impact’ evidence-based indicators that could be measured using routinely collected data (work package 1). In 89 general practices that shared data, we found marked variations and scope for improvement in adherence to several indicators (work package 2). Interviews with 60 general practitioners, practice nurses and practice managers explored perceived determinants of adherence to selected indicators and suggested the feasibility of adapting an implementation package to target different indicators (work package 3). We worked with professional and patient panels to develop four adapted implementation packages. These targeted risky prescribing involving non-steroidal anti-inflammatory and antiplatelet drugs, type 2 diabetes control, blood pressure control and anticoagulation for atrial fibrillation. The implementation packages embedded behaviour change techniques within audit and feedback, educational outreach and (for risky prescribing) computerised prompts. We randomised 178 practices to implementation packages targeting either diabetes control or risky prescribing (trial 1), or blood pressure control or anticoagulation (trial 2), or to a further control (non-intervention) group, and undertook economic modelling (work package 4). In trials 1 and 2, practices randomised to the implementation package for one indicator acted as control practices for the other package, and vice versa. A parallel process evaluation included a further eight practices (work package 5). Main outcome measures Trial primary end points at 11 months comprised achievement of all recommended levels of glycated haemoglobin, blood pressure and cholesterol; risky prescribing levels; achievement of recommended blood pressure; and anticoagulation prescribing. Results We recruited 178 (73%) out of 243 eligible general practices. We randomised 80 practices to trial 1 (40 per arm) and 64 to trial 2 (32 per arm), with 34 non-intervention controls. The risky prescribing implementation package reduced risky prescribing (odds ratio 0.82, 97.5% confidence interval 0.67 to 0.99; p = 0.017) with an incremental cost-effectiveness ratio of £2337 per quality-adjusted life-year. The other three packages had no effect on primary end points. The process evaluation suggested that trial outcomes were influenced by losses in fidelity throughout intervention delivery and enactment, and by the nature of the targeted clinical and patient behaviours. Limitations Our programme was conducted in one geographical area; however, practice and patient population characteristics are otherwise likely to be sufficiently diverse and typical to enhance generalisability to the UK. We used an ‘opt-out’ approach to recruit general practices to the randomised trials. Subsequently, our trial practices may have engaged with the implementation package less than if they had actively volunteered. However, this approach increases confidence in the wider applicability of trial findings as it replicates guideline implementation activities under standard conditions. Conclusions This pragmatic, rigorous evaluation indicates the value of an implementation package targeting risky prescribing. In broad terms, an adapted ‘one-size-fits-all’ approach did not consistently work, with no improvement for other targeted indicators. Future work There are challenges in designing ‘one-size-fits-all’ implementation strategies that are sufficiently robust to bring about change in the face of difficult clinical contexts and fidelity losses. We recommend maximising feasibility and ‘stress testing’ prior to rolling out interventions within a definitive evaluation. Our programme has led on to other work, adapting audit and feedback for other priorities and evaluating different ways of delivering feedback to improve patient care. Trial registration Current Controlled Trials ISRCTN91989345. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 8, No. 4. See the NIHR Journals Library website for further project information.