OBJECTIVE: Individuals with serious mental illness have high rates of cardiovascular disease (CVD) risk factors and mortality. This systematic review was conducted to evaluate pharmacologic and behavioral interventions to reduce CVD risk in adults with serious mental illness. DATA SOURCES: MEDLINE, EMBASE, PsycINFO, ClinicalTrials.gov, and Cochrane Database of Systematic Reviews were searched from January 1980 to July 2012 for English language studies. Examples of search terms used include schizophrenia, bipolar disorder, antipsychotics, weight, glucose, lipid, and cardiovascular disease. STUDY SELECTION: Two reviewers independently screened citations and identified 33 randomized controlled trials of at least 2 months' duration that enrolled adults with serious mental illness and evaluated pharmacologic or behavioral interventions targeting weight, glucose, or lipid control. DATA EXTRACTION: Reviewers extracted data, assessed applicability, and evaluated study quality; the team jointly graded overall strength of evidence. RESULTS: We included 33 studies. Most studies targeted weight control (28 studies). Compared with control groups, weight control was improved with behavioral interventions (mean difference = -3.13 kg; 95% CI, -4.21 to -2.05), metformin (mean difference = -4.13 kg; 95% CI, -6.58 to -1.68), anticonvulsive medications topiramate and zonisamide (mean difference = -5.11 kg; 95% CI, -9.48 to -0.74), and adjunctive or antipsychotic switching to aripiprazole (meta-analysis not possible). Evidence was insufficient for all other interventions and for effects on glucose and lipid control. The small number of studies precluded analyses of variability in treatment effects by patient characteristics. CONCLUSIONS: Few studies have evaluated interventions addressing 1 or more CVD risk factors in people with serious mental illness. Glucose- and lipid-related results were mainly reported as secondary outcome assessments in studies of weight-management interventions. Comparative effectiveness studies are needed to test multimodal strategies, agents known to be effective in nonserious mental illness populations, and antipsychotic-management strategies.