Aim: We aimed to study the prevalence of major risk factors for hepatocellular carcinoma (HCC) among Nigerians. Method: Eighty-five HCC patients and 77 non-HCC, nonchronic liver diseased age and gender-matched controls were recruited. The p53 codon 249mutationwas detected by restriction fragment length polymorphism (RFLP) using plasma DNA. HBV and HCV infection were detected by thirdgeneration enzyme-linked immunosorbent assay (ELISA) technique in 55 HCC subjects and 52 controls. Alcohol intake was obtained from the history of the subjects, and significant alcohol ingestion was taken as ingestion of >40 g daily of alcohol for >10 years. Results: The prevalence of the p53 codon 249 mutation, positive HBsAg status, anti-HCV, and significant alcohol ingestion among HCC patients were 7.6 (6/79), 58.2 (32/55), 6.0 (3/50), and 38.5% (30/78), respectively, versus 0 (0/73), 7.7 (4/52), 11.5 (6/52), and 13.3% (10/77), respectively among controls. The respective p values were 0.029, 0.000, 0.182, and 0.005. The odds ratio were 2.00 (95% CI: 1.70-2.35), 16.7 (95% CI = 5.276-52.857), 0.489 (95% CI = 0.115-2.073), and 4.186 (95% CI = 1.870-10.372), respectively. Conclusion: p53 codon 249 mutation, HBV infection, and alcohol are significantly associated with HCC in Nigeria, whereas HCV infection is not.