BACKGROUND: The underlying mechanisms of alcohol use disorder (AUD) are regarded to be strongly associated with genetic factors. Although great efforts have been made to identify the association of rs4680 polymorphism in the catechol-o-methyltransferase gene and risk to AUD, the outcomes were still inconsistent. This study is aimed at exploring the association of rs4680 polymorphism and AUD by using a meta-analysis approach. METHODS: Literature searching was undertaken across PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases. We set the search period before February 20, 2020. We used the Review Manager 5.3 (RevMan 5.3) software to estimate the effect sizes in five genetic models. RESULTS: In total, eighteen case-control studies and two cohort studies were included in this study. The merged results of overall population indicated there was no significant association between rs4680 polymorphism and AUD: V vs. M, OR = 1.02, 95% CI 0.93-1.12, = 0.70; VV vs. MM, OR = 0.99, 95% CI 0.79-1.23, = 0.92; VM vs. MM, OR = 0.91, 95% CI 0.81-1.03, = 0.15; VV+VM vs. MM, OR = 0.95, 95% CI 0.80-1.13, = 0.65; VV vs. VM+MM, OR = 1.04, 95% CI 0.91-1.18, = 0.57. Subgroup analysis by gender suggested rs4680 polymorphism was marginally associated with an elevated risk to AUD among males (VM vs. MM, OR = 0.81, 95% CI 0.67-0.98, = 0.03). However, subgroup analysis by race and diagnosis did not support any significant association. CONCLUSIONS: The present study suggests that rs4680 polymorphism has no association with AUD in the overall population, but it has a weak association with AUD in males. Carriers of VM genotype in males appear to have an increased risk to AUD.