Fifty-eight percent of hepatocellular carcinomas (HCCs) from Qidong, China, contain an AGG to AGT mutation at codon 249 of the p53 tumor suppressor gene, a mutation that is rarely seen in HCCs from Western countries. The population of Qidong is exposed to high levels of aflatoxin B-1 (AFB(1)), a fungal toxin that has been shown to induce the same mutation in cultured human HCC cells. To investigate the role of AFB(1) and of these p53 mutations in hepatocarcinogenesis, normal liver samples from the United States, Thailand, and Qidong (where AFB(1) exposures are negligible, low, and high, respectively) were examined for p53 mutations. The frequency of the AGG to AGT mutation at codon 249 paralleled the level of AFB(1) exposure, which supports the hypothesis that this toxin has a causative-and probably early-role in hepatocarcinogenesis.