Mean corpuscular volume (MCV) evolution during cytotoxic therapy was studied in 32 patients with Hodgkin's disease (HD) who developed therapy-related acute nonlymphocytic leukemia (t-ANLL) and in 64 HD controls matched for age, therapy duration, and MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) administration. Maximum MCV during therapy reached 108.3 +/- 8.2 fl in t-ANLL patients and 103.4 +/- 9.1 fl in the controls (P = 0.001). Maximum MCV increase was 26.7 +/- 8.3 fl in t-ANLL patients and 16.6 +/- 8.3 fl in the controls (P = 10(-9). The greatest 3-month increase observed during therapy was 14.8 +/- 6 fl in the t-ANLL patients and 10.1 +/- 4.8 fl in the controls (P = 0.0001). During initial MOPP therapy, the greatest 3-month increase reached 14.1 +/- 5.3 fl in t-ANLL patients and 9.8 +/- 4.5 fl in the controls (P = 0.01). The relative risk of developing t-ANLL was 9 for a MCV maximum increase over 24 fl during therapy, which was observed in 71% of the patients with t-ANLL and in only 22% of the controls. For the greatest 3-month MCV increase over 15 fl observed in 57% of the t-ANLL patients and in 17% of the controls, the relative risk reached 15. This suggests that there is at least one factor, independent from therapy, which predisposes to t-ANLL. MCV evolution during therapy appears useful in determining which HD patients have a high risk of developing t-ANLL.