To understand the relationship between the L-myc genotypes and esophageal cancer risk, a polymerase chain reaction-based restriction fragment length polymorphism analysis was performed on 91 Japanese patients with esophageal cancer and 241 non-cancer outpatients. No significant difference in the distribution of genotypes was observed between patients and controls; 18.7% LL genotype, 56.0% LS and 25.3% SS among patients, and 24.5%, 55.6% and 19.9%, respectively, among controls. Frequency of the s-allele in patients (0.533) was slightly higher than in controls (0.477), but the difference was not statistically significant. However, the odds ratios (ORs) for smoking or heavy drinking were markedly higher in SS and LS genotypes than in LL genotype; age-sex-adjusted ORs for smoking was 7.57 in the SS genotype, 6.40 in the LS genotype and 1.77 in the LL genotype. Age-sex-adjusted ORs for heavy drinking were 19.78, 18.20 and 7.40, respectively. The age-sex-adjusted ORs for both factors combined were 12.77, 18.45 and 1.44, respectively. These results suggested that the L-myc polymorphism might modify the effects of lifestyle factors on esophageal cancer risk.