Mouse B16 melanoma cells rapidly develop resistance to the antiproliferative effects of interferon alpha (IFN alpha) and interferon beta (IFN beta) when they are exposed to the interferons in vitro. This resistance was characterized to be non-genetic and dose-dependent, and does not alter other IFN-induced effects such as antiviral effects and elevation of 2',5'-oligoadenylate synthetase activity in IFN-treated cells. The study of these IFN-resistant cells has been extended to an in vivo tumor model. Resistance, if it occurred in vivo, did not adversely affect the survival of IFN-treated mice. Further, IFN-treated mice inoculated with B16 cells that were resistant in vitro (B16 alpha res cells) survived significantly longer than IFN-treated mice inoculated with B16 cells that were sensitive in vitro. The IFN-treated B16 alpha res-inoculated mice had a significantly higher cure rate as well. The prolonged survival of the mice bearing B16 alpha res cell tumors did not seem to be caused by the slower growth rate of the B16 alpha res cells, since experiments performed with a tenfold higher B16 alpha res cell inoculum and a tenfold lower B16 cell inoculum did not show any change in the survival pattern. It is clear that in vitro resistant B16 alpha res cells are more sensitive to antitumor effects induced by IFN in vivo than in vitro sensitive B16 cells.