Colchicine is an ancient anti-inflammatory drug. In recent years, an increasing number of studies have shown that colchicine improves the prognosis of patients with coronary artery disease (CAD), while other studies have reported the opposite. The aim of this study was to evaluate the relative efficacy and safety of colchicine in treating CAD. PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov were searched from inception to 20 October 2020 for randomized controlled trials (RCTs) comparing colchicine and placebo in patients with CAD. The primary outcomes were the primary composite outcomes of cardiovascular death, myocardial infarction (MI), ischemic stroke, or ischemia-driven coronary revascularization after colchicine administration. The secondary outcomes were cardiovascular death, death from any cause, noncardiac death, MI, ischemic stroke, coronary revascularization, gastrointestinal (GI) symptoms, and the different effects of colchicine in acute and chronic CAD. We assessed the pooled odds ratio (OR) of all-cause and cardiovascular mortality for CAD in fixed-effects models, the pooled risk ratio (RR) of the primary composite outcomes, MI, ischemic stroke, and ischemia-driven coronary revascularization in fixed-effects models and the pooled RR of GI symptoms in random-effects models. The Cochrane risk of bias tool was used to assess the risk of bias in the included RCTs. Eleven of the 894 identified studies (n = 12,899 patients) were included (6501 subjects in the colchicine group; 6389 subjects in the control group). The colchicine group had significantly lower pooled RRs of the primary composite outcomes (0.73, 95% confidence interval (CI) 0.64-0.84, P < 0.0001), MI (0.77, 95% CI 0.64-0.92, P = 0.004), ischemic stroke (0.47, 95% CI 0.30-0.76, P = 0.002), and ischemia-driven coronary revascularization (0.77, 95% CI 0.66-0.89, P = 0.0007), while the pooled RR of adverse GI events (2.15 95% CI 1.40-3.31, P = 0.0005) was significantly higher. Colchicine had a lower pooled RR of ischemic stroke (0.28, 95% CI 0.12-0.65, P = 0.003) for patients with acute compared with chronic CAD. Colchicine treatment significantly decreased the risk of primary cardiovascular composite outcomes, MI, ischemic stroke, and ischemia-driven coronary revascularization in CAD patients but increased adverse GI events. There was no significant difference in all-cause mortality, cardiovascular mortality, and non-cardiovascular death between the colchicine and control groups. Colchicine performs better in acute CAD patients with ischemic stroke than chronic CAD patients. Colchicine might be a new treatment for patients with CAD. © 2022. International League of Associations for Rheumatology (ILAR).