The CMF regimen, which is clinically used in adjuvant therapy of breast cancer, is known to be carcinogenic in rats (Habs and Schmähl, 1981). To examine alternative regimens, a long-term carcinogenicity study was performed, using the VMF regimen as follows: V (i.v.), M (i.p.) and F (p.o.) at 0.8, 20 and 300 mg/m2, respectively. These doses and a half-dose regimen (0.5 VMF) were administered every 6 weeks to 80 rats (40 males, 40 females) in each of three groups. Group I served as an untreated control. Groups II, III and IV received 6 X VMF, 18 X 0.5 VMF and 18 X VMF, respectively. Unlike treatment with comparable doses of CMF, the present therapy did not result in an increased tumor rate or a change in tumor type over controls. The chemotherapeutic efficacy of VMF was compared with that of CMF by administering the following doses (mg/m2 i.p.) to groups of 20 rats bearing methylnitrosourea-induced primary mammary carcinomas: group 1:C (420), 2:V (2.1), 3:M (35) and F (350), 4:C (210), M (21) and F (280), 5:V (1.05), M (21) and F (280), 6: as in 4 except that C was given 24 h prior to M and F, 7: as in 5 except that V was given 24 h prior to M and F, 8: ovariectomy on day 1, 9: control group. Animals bearing a tumor volume of greater than or equal to 0.8 cm3 were randomly allocated to the individual groups (day 1) and subsequently treated on days 1, 8, 15 (V only) 22, and 29. After 5 weeks the following T/C values were recorded: group 1: 12.6%, 2: 80%, 3: 49%, 4: 42.8%, 5: 67%, 6: 49.2%, 7: 26.5%, 8: 45.5%. These results indicate a possible superiority of VMF over CMF, since the former exhibits little or no carcinogenicity at comparable therapeutic activity.