BACKGROUND Mouse double minute 4 (MDM4) has been extensively investigated as a negative regulator of P53, its negative feedback loop, and the effect of its genetic polymorphisms on cancers. However, many studies showed varying and even conflicting results. Therefore, we employed meta-analysis to further assess the intensity of the connection between MDM4 polymorphisms and malignancies. MATERIAL AND METHODS We searched eligible articles in 5 databases (Cochrane Library, PubMed, Web of Science, Wan Fang Database, and China National Knowledge Infrastructure) up to August 2021. Odds ratios (ORs) and 95% confidence intervals (CIs) were utilized to probe the correlation of 5 MDM4 polymorphisms (rs4245739, rs1563828, rs11801299, rs10900598, and rs1380576) with carcinomas. We employed meta-regression and subgroup analysis to probe for sources of heterogeneity; Funnel plots, Begg's test, and Egger's test were used to evaluate publication bias. Sensitivity analysis was applied to assess the stability of the study. RESULTS Twenty-two studies, comprising 77 reports with 29 853 cases and 72 045 controls, were included in our meta-analysis. We found that rs4245739 polymorphism was a factor in reducing overall cancer susceptibility (dominant model, OR=0.85, 95% CI=0.76-0.95; heterozygous model, OR=0.86, 95% CI=0.78-0.96; additive model, OR=0.87, 95% CI=0.79-0.95), especially in Asian populations, and it also reduces the risk for esophageal squamous cell carcinoma (ESCC). The remaining 4 SNPs were not associated with cancers. CONCLUSIONS The rs4245739 polymorphism might reduce the risk of malignancies, especially in Asian populations, and it is a risk-reducing factor for ESCC incidence. However, rs1563828, rs11801299, rs10900598, and rs1380576 are not relevant to cancer susceptibility.