BackgroundDespite the fact that several studies have investigated the association between serum copper levels (S-Cu) and the risk of cardiovascular diseases, this relationship remains unclear. The aims of this study were to investigate the association between S-Cu and risk of major adverse cardiovascular events (MACE), including total stroke, ischemic stroke, hemorrhagic stroke, myocardial infarction and cardiovascular mortality, and identify potential sources of results heterogeneity.MethodsWe carried out a systematic review and meta-analysis. The selection criteria were: (1) Observational studies (cohort studies, case-control studies and hybrid studies); (2) Studies containing quantitative data about the relationship between S-Cu and risk of MACE; (3) Estimating association measures; and (4) Studies written in English, French or Spanish. Overall pooled Odds ratio (pOR) and 95% confidence intervals (95% CI) of MACE for the highest vs. lowest S-Cu category were calculated using random-effects models.ResultsSixteen studies with a total of 41,322 participants were included in the meta-analysis: 10 prospective cohort studies, 5 nested case-control studies and 1 case-control study. Comparing highest vs. lowest category, high S-Cu levels were associated with total stroke (pOR: 1.49, 95% CI 1.22–1.82;I2= 0%,p= 0.54), myocardial infarction (pOR: 1.31, 95% CI 1.17–1.46;I2= 0.0%,p= 0.92) and cardiovascular mortality (pOR: 1.60, 95% CI 1.39–1.86;I2= 0.0%,p= 0.54). Subgroup analysis showed that studies with a hybrid design had higher risks for cardiovascular mortality (pOR: 3.42, 95% CI 1.98–5.92) and ischemic stroke (pOR: 1.54, 95% CI 1.30–1.83).ConclusionHigh S-Cu levels were associated with an increased risk of total stroke, myocardial infarction and cardiovascular mortality. Hybrid studies seems to modify the strength of the association between S-Cu and the risk of cardiovascular mortality and ischemic stroke.Systematic review registration[https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022370782], identifier [CRD42022370782].