An in vitro model of acute and chronic infections with feline immunodeficiency virus (FIV) was used to examine the effect of two immunosuppressive agents, cyclosporin A (CsA) and tacrolimus (also known as FK506), on the inhibition of the replication of the virus and of apoptosis. Both drugs significantly suppressed virus production in a dose-dependent manner in acutely and chronically infected cells. The ability of FK506 to inhibit virus replication was much lower than that of CsA, and was accompanied by marked antiproliferative activity. Treatment of infected cells with either CsA or FK506 did not affect the rise of free intracellular Ca2+ but did protect the cells against apoptosis. Thus, the antiviral activity of CsA and FK506 makes these compounds promising candidates for the development of drugs suitable for the treatment of AIDS.