Tumor DNA content has been described as having prognostic significance in patients with colorectal carcinoma. It has been unclear, however, whether tumor ploidy as a prognostic factor is independent of various standard prognostic variables such as depth of invasion and lymph node involvement by the tumor. We retrospectively examined 77 patients who were diagnosed between 1974 and 1980 as having had resectable Dukes' stage A, B, or C colorectal carcinomas. The DNA content of each tumor was analyzed by flow cytometry on paraffin-embedded specimens. Both for aneuploid stage B tumors and for the entire group of aneuploid tumors, the disease-free and overall survival times of the patients were significantly shorter than those of patients with diploid colorectal carcinomas. Logistic regression analysis demonstrated that aneuploidy was an independent prognostic variable in predicting recurrent disease as well as death from the colorectal cancer. Tumor ploidy was, in fact, the single most important prognostic factor among all of the clinical and pathologic variables studied. Thus, the DNA content of colorectal carcinoma appears to play an important role in indicating the biologic aggressiveness of the disease.