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Background: The association between epidermal growth factor (EGF) gene +61A/G polymorphism (rs4444903) and hepatocellular carcinoma (HCC) susceptibility has been widely reported, but the results were inconsistent. To clarify the effect of this polymorphism on HCC risk, a meta-analysis was performed. Methods: The PubMed, Embase, Cochrane Library, Web of Science, Chinese BioMedical Literature (CBM), Wanfang and Chinese National Knowledge Infrastructure (CNKI) databases were systematically searched to identify relevant studies published up to December 2013. Data were extracted independently by two authors. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to assess the strength of association. Results: A total of 16 studies including 2475 HCC cases and 5381 controls were included in this meta-analysis. Overall, a significantly increased HCC risk was observed under all genetic models (G vs. A: OR = 1.383, P < 0.001, 95% CI: 1.174-1.629; GG vs. GA + AA: OR = 1.484, P < 0.001, 95% CI: 1.198-1.838; GG + GA vs. AA: OR = 1.530, P < 0.001, 95% CI: 1.217-1.924; GG vs. AA: OR = 1.958, P < 0.001, 95% CI: 1.433-2.675; GA vs. AA: OR = 1.215, P = 0.013, 95% CI: 1.041- 1.418). In the subgroup analyses by ethnicity, a significant association with HCC risk was found in Asian populations (G vs. A: OR = 1.151, P = 0.001, 95% CI: 1.056-1.255), European populations (G vs. A: OR = 1.594, P = 0.027, 95% CI: 1.053-2.413, and African populations (G vs. A: OR = 3.599, P < 0.001, 95% CI: 2.550-5.080), respectively. Conclusions: Our study shows that EGF +61A/G polymorphism is significantly associated with the increased HCC risk, especially in Asian populations. Further large-scale and well-designed studies are required to confirm this conclusion. [ABSTRACT FROM AUTHOR]