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Recent evidence questioned the overall safety and efficacy of colchicine in patients with coronary artery disease (CAD), as novel evidence focusing on acute coronary syndromes (ACSs) gave neutral results, while trials focusing on chronic coronary syndrome supported colchicine administration to improve long-term outcomes. However, no study has ever explored whether there is a true therapeutic difference across the populations or these discrepancies are due to additional confounders. Against this background, we performed a systematic review and meta-analysis of randomized trials of colchicine in patients with CAD. The primary endpoints were trial-defined major adverse cardiovascular events (MACE) and serious adverse events (SAEs). Secondary endpoints included all-cause death, measures of ischemia (cardiovascular death, myocardial infarction [MI], any revascularization, stroke) and measures of safety (serious infections or sepsis and gastrointestinal adverse events). All analyses included an interaction term for the clinical presentation. Sensitivity analyses were performed to explore sources of heterogeneity. After literature search, 20 trials encompassing a total of 21,486 patients (65.4% ACS) were included. Colchicine significantly reduced MACE (incidence rate ratio [IRR]: 0.70; 95% CI 0.55-0.87) without increasing risk for SAEs. Colchicine also reduced MI (IRR 0.81; 95% CI 0.70-0.94) and any revascularization (IRR 0.71; 95% CI 0.51-0.99), while increasing the risk of gastrointestinal adverse events (IRR 1.68; 95% CI 1.23-2.28). No statistically significant interaction was noted for clinical presentation for any endpoint, but a significant interaction for the drug dosage administered and the relationship with the COVID-19 pandemic was noted. In conclusion, the use of colchicine in patients with CAD reduces MACE without significantly increasing SAEs compared to control, although increasing gastrointestinal adverse events, without interaction by clinical presentation.