Squamous cell lung carcinomas (SCCs) represent a highly malignant group of tumors, and effective treatment is greatly dependent upon early diagnosis. However, objective diagnosis of atypia is difficult and useful markers need to be defined. In this study, genomic instability, cell proliferation, and cellular accumulation of mutant p53, as reflected by DNA aneuploidy, proliferating cell nuclear antigen, and p53 immunoreactivity, respectively, were evaluated in bronchial squamous metaplasia without atypia (n = 4), bronchial squamous metaplasia with low-grade atypia (n = 12), bronchial squamous metaplasia with high-grade atypia (n = 15), early-stage SCC (n = 15), and advanced-stage SCC (n = 33). Our results suggest that hyperproliferation is an early event followed by DNA aneuploidy, which in turn precedes p53 immunoreactivity in the genesis of SCC. We conclude that routine assessment of proliferating cell nuclear antigen, DNA ploidy, and p53 may be valuable for the early diagnosis of SCC.