Effective treatment to achieve target lipid parameters in high-risk patients may require combination drug therapies. Concerns regarding risks associated with such combination therapies may limit their use. A systematic overview of randomized controlled trials to assess risks associated with combination statin and ezetimibe therapy was performed. Eighteen trials were identified, including 14,471 patients. Follow-up ranged from 6 to 48 weeks. Compared with statin monotherapy, combination therapy did not result in significant absolute increases in risks of myalgias (risk difference -0.033, 95% confidence interval [CI] -0.06 to -0.01), creatine kinase increases (risk difference 0.011, 95% CI -0.02 to 0.04), rhabdomyolysis (risk difference -0.003, 95% CI -0.01 to 0.004), transaminase increases (risk difference -0.003, 95% CI -0.01 to 0.005), gastrointestinal adverse events (risk difference 0.005, 95% CI -0.03 to 0.04), or discontinuations because of an adverse event (risk difference -0.005, 95% CI -0.03 to 0.02). In conclusion, based on available randomized trials, the addition of ezetimibe to statin therapy did not increase the risk of myalgias, creatine kinase increases, rhabdomyolysis, transaminase increases, gastrointestinal adverse events, or discontinuations because of an adverse event. Additional trials are necessary to ensure that results of clinical trials are consistent with routine clinical practice, particularly in older patients with more co-morbid conditions and patients on higher statin doses.