Although the short arm of chromosome 17, which contains the p53 gene, is frequently affected by loss of heterozygosity (LOH) in lung cancer, little is known about similar changes on the long arm. We found that LOH affected one or more of six loci along chromosome 17 in 59% of 102 informative non-small cell lung cancer (NSCLC) cases. Specifically, the frequency of LOH at 17q was 42%, approaching that at 17p (54%), and two distinct 17q regions were implicated. LOH at D17S4 on 17q was more frequent in adenocarcinomas than in squamous cell carcinomas, whereas squamous cell carcinomas had more LOH at 17p than at 17q, findings that indicate molecular genetic heterogeneity between the major NSCLC subtypes. In addition, LOH at 17q correlated with higher T stages and a significantly worse prognosis. In comparison, 25% of cases had mutations of p53 exons 5-8 but these were not associated with stage or survival. The data suggest that independent of p53, there are important tumor suppressor gene(s) on 17q that may influence NSCLC pathogenesis, progression, and survival.