The interaction of doxorubicin and N-trifluoroacetyladriamycin-14-valerate (AD32) with B16 melanoma cell variants that exhibit distinct metastatic properties was explored. The addition of the two drugs to cell monolayers at noncytolytic concentrations for 16 hours resulted in irreversible inhibition of proliferation of tumor cells and loss of their tumorigenicity after injection into inbred C57BL/6 mice. Cessation of melanoma cell proliferation was accompanied by cellular and nuclear hypertrophy and the development of axon-like processes. As assessed by drug-specific cytofluorescence, after 16-hour exposure of the cells to doxorubicin and AD32, the drugs were localized in the nuclei. Incubation of drug-treated cell monolayers for 6 additional days in drug-free culture medium led to the complete disappearance of nuclear stain. The highly metastatic B16-F10-B2 cell line was the most sensitive to the drugs' effects, whereas the other two malignant melanoma cell lines, although differing in their metastatic capabilities, exhibited similar sensitivities to the drugs' effects. Doxorubicin was notably more potent than AD32 in its growth inhibitory effect on the three tested melanoma cell variants. The possible mutagenic effect of anthracycline drugs on tumor cells was discussed.