Despite advancements in medical and interventional therapy, patients with cardiovascular disease (CVD) continue to have residual risk for recurrent cardiovascular events. Colchicine has a unique antiinflammatory mechanism that has generated interest in its potential use as a secondary cardiovascular preventive therapy. The objective of this systematic review was to evaluate the evidence for long-term (6 months or more) colchicine therapy in patients with established CVD. A search of Medline and Embase from inception to February 2020 was performed. Included were randomized controlled trials (RCTs) or propensity score-matched observational studies that compared colchicine (at any dose) with placebo or no treatment. Outcomes of interest included any major adverse cardiovascular event, cardiovascular hospitalization, coronary artery restenosis, cardiovascular death, or all-cause death. Five RCTs were included. The dose of colchicine ranged from 0.5 mg/day to 0.6 mg twice/day, and follow-up ranged from ~6-36 months. Two trials (one double blind and one single blind) showed a reduction in composite outcomes of major adverse cardiovascular events. One study failed to demonstrate a benefit with colchicine in restenosis or recurrent ischemia after angioplasty; however, it was conducted before the routine use of modern percutaneous coronary intervention and medical therapies. In contrast, a more recent trial found that colchicine reduced the rate of in-stent restenosis in patients who received a bare metal stent. Finally, one trial in patients with heart failure with reduced ejection fraction did not observe a benefit in death or heart failure hospitalization with colchicine despite a reduction in inflammatory markers. No trial demonstrated a reduction in cardiovascular or all-cause death, and most trials showed an increase in the rate of diarrhea with colchicine. Overall, colchicine has demonstrated promising results for the secondary prevention of CVD; however, further studies are required to confirm these findings before colchicine can be routinely recommended in practice. © 2020 Pharmacotherapy Publications, Inc.