The association between rs738409 (C > G, 48M) with patatin-like phospholipase domain-containing 3 (PNPLA3) gene and the risk of hepatocellular carcinoma (HCC) was controversial in different ethnic populations. Our study aimed to explore the effect of PNPLA3 rs738409 on the risk of HCC and persistent infection of Hepatitis B virus (HBV) in a Chinese HBV-related population, and further evaluate its role in HCC risk among Asians. First, we performed a case-control study by recruiting 786 HBV-related HCC cases, 695 HBV persistent carriers and 719 HBV natural clearance subjects. PNPLA3 rs738409 was genotyped by MassARRAY platform. Second, we conducted a systematic review and meta-analysis on Asians to further validate our results. Our case-control study demonstrated that PNPLA3 rs738409 was not associated with HCC risk or persistent HBV infection (All P > 0.05). The subsequent meta-analysis included 13 Asian studies with 9,802 subjects. Results showed that PNPLA3 rs738409 might increase HCC risk among healthy subjects (pooled odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.11-1.95), but it had no influence on the development of HCC among HBV-related subjects (pooled OR = 1.07, 95%CI = 0.89-1.30). Our case-control study highlights that PNPLA3 rs738409 is probably not associated with the risk of HCC or persistent HBV infection in a Chinese HBV-related population. Besides, our systematic review and meta-analysis on Asians further suggest that PNPLA3 rs738409 may confer an increased risk of HCC among healthy people, but contribute little to the development of HCC among HBV-related subjects. Future studies are required to confirm these results.