DNA content analysis by flow cytometry was performed in 32 patients with plasma cell myeloma and 3 patients with Waldenstrom's macroglobulinemia to determine the biologic and potential clinical usefulness of this technique. Hyperdiploid tumor DNA content was found in 23 myeloma patients (72%) during the course of illness, including 16/28 at presentation, but in none of 3 patients with Waldenstrom's macroglobulinemia. There was no significant association of aneuploidy in myeloma patients with age, sex, race, or M-protein class. Myeloma patients with aneuploid tumor cells were more likely to have advanced stage (p = 0.032) than patients with diploid plasma cells, and all patients with renal failure had aneuploid tumors. Pretreatment factors significantly associated with survival included stage (p = 0.01), serum creatinine (p = 0.003), and tumor DNA content (p = 0.005). Multivariate analysis using the Cox life table regression procedure indicated that the significant relation of tumor DNA content with survival remained after adjusting for stage (p less than 0.005). Myeloma patients with diploid tumors at diagnosis frequently had aneuploid plasma cells at the time of relapse, indicating a possible relationship of chromosomal alterations in the tumor to clinical drug resistance. We conclude that aneuploid tumor cells at the time of diagnosis of myeloma are of independent prognostic significance, and the development of aneuploidy is a frequent occurrence at clinical relapse, suggesting the change in DNA content are of biologic and clinical significance.