The anti-Friend leukemia virus (FL V) effects of interferon-a-A/D (IFN-α) and 2‘,3’-didehydro-2‘,3’-dideoxythymidine (stavudine) used alone and in combination were examined in Mus dunni cells using a checkerboard-type experiment design. Strong antiviral synergy and a suggested cytotoxic synergy were seen. In two experiments to evaluate the effect of combining therapy with IFN-a and stavudine against FLV disease in the hybrid mouse in (B10.A 'd7 A.By)F1 which is a strong producer of cytotoxic T cells, the drug combination resulted in better inhibition of FLV disease than did either drug used alone. Combination therapy inhibited splenomegaly, splenic virus infectious centers, plasma virus, and the virus-induced increase in hematocrit to a greater degree than did either drug alone. These data indicate that combination therapy with stavudine and IFN-α is effective in the treatment of murine retrovirus infections and may be of value in the treatment of human AIDS.