Background <p>Colchicine has been incorporated into major clinical guidelines for the secondary prevention of cardiovascular disease (CVD). However, recent randomized trials have presented contradictory results.</p> Objective <p>We aimed to synthesize the current evidence on colchicine in secondary CVD protection, using a cumulative-dose approach.</p> Methods <p>We conducted a meta-analysis incorporating all randomized controlled trials (RCTs) globally. RCTs directly comparing colchicine versus placebo/standard care for the secondary prevention of cerebrovascular or coronary vascular disease were included. Odds ratios (OR) were derived for the primary outcome, defined as the prospective occurrence of major adverse cardiovascular events (MACE). Secondary outcomes included mortality, individual components of MACE, C-reactive protein, and adverse effects.</p> Results <p>In total, 14 RCTs including 31,397 participants were included. Colchicine significantly reduced MACE (OR 0.80; 95% confidence interval [CI] 0.68–0.94) in both acute atherothrombotic CVD and all CVD (OR 0.72; 95% CI 0.60–0.86) and resulted in significant prospective reductions in C-reactive protein. The threshold effect was apparent, with a protective benefit of colchicine against MACE at higher cumulative exposure ≥ 90 mg-days (OR 0.66; 95% CI 0.52–0.84). Colchicine resulted in no differences in cardiovascular or non-cardiovascular mortality.</p> Conclusions <p>Colchicine significantly reduces MACE in both acute atherothrombotic and all CVD across multiple ethnicities, with a threshold protective effect that clinically corresponds to treatment with 0.5 mg daily for at least 6 months. Importantly, there was no signal of increased all-cause mortality.</p> Registration <p>PROSPERO identifier no. CRD420251003142.</p>