Most nonimmune patients with Plasmodium falciparum infection are no longer cured by such standard antimalarial drugs as chloroquine. Thus, alternative treatment regimens are necessary. A combination therapy was tested consisting of a subcurative dose of chloroquine and interferon-gamma (IFN-gamma) in BALB/c mice with lethal Plasmodium vinckei malaria. Treatment with either agent alone prolonged median survival by 1-2 days compared with placebo-treated mice. However, a combination of 80 micrograms of chloroquine given at the time of infection plus 1 x 10(4) units of IFN-gamma/day for 11 days (starting 3 days before infection) cured 83% of infected mice. Moreover, these mice showed solid immunity when challenged with the homologous strain of P. vinckei. However, when these mice were infected with the heterologous strain of Plasmodium berghei, the same degree of parasitemia developed as did in P. berghei-infected control mice. Thus, the combination of chemotherapy with the cytokine IFN-gamma leads to substantial improvement of antimalarial treatment and to a rapid development of strain-specific immunity in murine P. vinckei malaria.