We compared the frequency of loss of heterozygosity on all autosomal chromosomes among 41 squamous cell carcinomas and 119 adenocarcinomas, to analyze possible relationships of specific tumor suppressor gene(s) to each histological type. On the majority (28 of 36) of chromosomal arms tested, loss of heterozygosity was observed more frequently in squamous cell carcinomas than in adenocarcinomas; in nine of these locations (3p, 3q, 4q, 7p, 9q, 13q, 16q, 17p, and 21q), the frequency was statistically significant (3p, 3q, 4q, 9q, 13q, and 17p, P < 0.01; 7p, 16q, and 21q, P < 0.05, chi 2 test). In squamous cell carcinomas, the frequency of allelic loss on chromosome 9q (67%) fell between the frequencies of loss on chromosomes 3p (82%) or 17p (88%) and chromosome 13q (60%). On the other hand, in adenocarcinomas frequent loss of heterozygosity was observed on chromosomes 8q (32%), 9p (36%), 3p (40%), and 17p (51%). Furthermore, allelic losses on chromosomes 9p, 9q, and 13q tended to correlated with smoking. These results suggest that more genetic changes accumulate during tumorigenesis in squamous cell carcinomas than in adenocarcinomas and that unidentified tumor suppressor genes exist on chromosome 9q for squamous cell carcinoma and on chromosome 8q for adenocarcinoma of the lung. These differences may be related to differences in tumorigenic mechanisms, such as etiological factors, operating in the separate histologies.