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Background: Currently, there is a lack of information on the comparative efficacy and safety of non-statin lipid-lowering agents (NST) in cardiovascular (CV) disease risk reduction when added to background statin therapy (ST). This study determine the relative treatment effects of NST on fatal and non-fatal CV events among statin-treated patients.Methods: A network meta-analysis based on a systematic review of randomized controlled trials (RCTs) comparing non-statin lipid-modifying agents among statin-treated patients was performed. PubMed, EMBASE, CENTRAL, and Clinicaltrial.gov were searched up to April 10, 2018. The primary outcomes were CV and all-cause mortalities. Secondary CV outcomes were coronary heart disease (CHD) death, non-fatal myocardial infarction (MI), any stroke, and coronary revascularization. Risks of discontinuations were secondary safety outcomes.Results: Sixty-seven RCTs including 259,429 participants with eight interventions were analyzed. No intervention had significant effects on the primary outcomes (CV mortality and all-cause mortality). For secondary endpoints, proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK) plus statin (PCSK/ST) significantly reduced the risk of non-fatal MI (RR 0.82, 95% CI 0.72–0.93, p = 0.003), stroke (RR 0.74, 95% CI 0.65–0.85, p < 0.001), coronary revascularization (RR 0.84, 95% CI 0.75–0.94, p = 0.003) compared to ST. Combinations of ST and all NST except PCSK and ezetimibe showed higher rate of discontinuation due to adverse events compared to ST.Conclusions: None of NST significantly reduced CV or all-cause death when added to ST. PCSKs and to a lesser extent, ezetimibe may help reduce cardiovascular events with acceptable tolerability profile among broad range of patients.