Background: People with severe mental illness die 15-20 years earlier than the general population. This excess mortality is explained largely by preventable physical health conditions. Evaluating the effectiveness of interventions that target risk behaviours in people with SMI is a global health priority. Interventions focussing on single behaviours may be ineffective in changing health outcomes. No systematic review has compared the effectiveness of targeting multiple or single risk behaviours in this population. Methods: We searched Cochrane Central Register of Controlled Trials (CENTRAL), Embase, MEDLINE, PsycINFO and Science Citation Index in March 2020 and Applied Social Science Index and Abstracts (ASSIA) in September 2020. We included randomised controlled trials of single or multiple health risk behaviour interventions in people with SMI. The study is registered on PROSPERO (CRD42018104724). We conducted network meta-analyses to compare effectiveness of interventions targeting multiple and single risk behaviours. Findings: We included 67 RCTs. Just over half of studies had high overall risk of bias. Trials focusing on smoking alone led to greater smoking abstinence than targeting smoking and other behaviours. However, heterogeneity means we cannot rule out other interpretations explanations. For weight loss (e.g. any risk behaviour intervention: -2.10 kg, 95% CrI -3.14, -1.06) and BMI (e.g. any risk behaviour intervention: -0.49, 95% CrI -0.97, -0.01) all risk behaviour interventions had positive but modest benefits compared with treatment as usual. There were potential synergies for targeting multiple health behaviours for reduction in systolic blood pressure. We found no evidence of a deterioration in mental health for people with SMI engaging in these interventions. Interpretation: Multiple and single risk behaviour interventions were associated with positive but modest benefits. Targeting smoking alone appeared to be more effective, but few studies assessed behavioural outcomes. Interventions were not associated with deterioration in mental health. Funding: National Institute for Health Research Declaration of Interest: We declare no competing interests.