We determined the polymorphic N-acetyltransferase 2 (NAT2) genotype of 124 patients with non-small-cell lung cancer (NSCLC) and 376 control subjects using a PCR-based assay. The slow acetylator genotype was present in 17 (14%) of 124 NSCLC patients and in 40 (11%) of 376 control subjects. The relative risk of slow acetylators compared with rapid acetylators in patients with adenocarcinoma was 2.01 (p = 0.05). This trend was more marked when the analysis was confined to patients under the age of 65 (relative risk, 2.7; p = 0.03). No such trend was identified in patients with squamous cell carcinoma. We also determined the incidence of p53 gene mutations to investigate the possibility of a link between this gene mutation and N-acetylation polymorphism. There was no significant association between p53 gene mutations and NAT2 polymorphism in the overall NSCLC group. However, the incidence of p53 mutations in adenocarcinoma patients under the age of 65 who had the slow acetylator genotype was 63% compared with 38% in patients with the rapid or intermediate acetylator genotype. These findings suggest that the slow acetylator phenotype may be linked to the impaired metabolism of a carcinogen that predisposes individuals to p53 gene mutations, and thus may be associated with an increased risk of pulmonary adenocarcinoma.