The association of L-myc polymorphism with cancer susceptibility and prognosis has produced conflicting results. This may have been due to racial/ethnic differences and methodological variations in the studies, such as, control selection and case stratification. Therefore, we investigated the genotype distribution of the L-myc polymorphism in 169 lung cancer patients and 169 non-cancer controls, and analyzed the association of this polymorphism with cancer susceptibility and prognosis in relation to age-specific controls as well as stratified cases. The genotype frequencies in the Taiwanese non-cancer controls were 0.56 (L) and 0.44 (S). Chi-square (chi(2)) analysis indicated a significant difference in the Taiwanese genotype distribution of L-myc compared with that of African-Americans (P=0.001). Logistic regression analysis of cases/controls, adjusted for both age and sex, indicated that an increased frequency of the LL genotype was observed in early-staged patients compared with the non-cancer controls (OR=0.43, 95% CI, 0.20-0.94, P=0.03). In addition, the frequency of the LL genotype was significantly higher in stages I+II patients (47.4%) than in stages III+IV patients (28.4%) (P=0.05). Furthermore, the S allele frequency was significantly increased in stages III+IV patients (P=0.005). As both L-myc and p53 polymorphisms were analyzed for their prognostic value, the patients with an S allele of the L-myc gene and a Pro/Pro variant genotype of the p53 gene had significantly poorer prognoses compared with other patients (P=0.004, by the log rank test). These data suggest that the S allele of the L-myc polymorphism may be associated with lung cancer progression.