The therapeutic efficacies of human recombinant alpha interferon (IFN-alpha), IFN-alpha plus zidovudine (AZT), and AZT alone were evaluated in presymptomatic cats with established feline leukemia virus (FeLV)-acquired immunodeficiency syndrome (FAIDS) infection and high levels of persistent antigenemia. Subcutaneous injection of 1.6 x 10(6) U of human recombinant IFN-alpha 2b per kg delivered peak concentrations in plasma of 3,600 U/ml at 2 h postadministration with a half-life of elimination of 2.9 h. This dosage of IFN-alpha could be delivered to cats for up to 12 weeks without significant clinical toxicity. Oral administration of AZT (20 mg/kg three times daily) resulted in peak concentrations in plasma of 3 micrograms/ml at 2 h with a half-life of elimination of approximately 1.60 h. Treatment of FeLV-FAIDS-infected cats with IFN-alpha, either alone or in combination with orally administered AZT, resulted in significant decreases in circulating p27 core antigen beginning 2 weeks after the initiation of therapy. AZT alone had no effect on circulating virus antigen. Depending upon whether high (1.6 x 10(6) U/kg)- or low (1.6 x 10(4) to 1.6 x 10(5) U/kg)-dosage IFN-alpha was used, cats became refractory to therapy 3 or 7 weeks after the beginning of treatment. At these times, IFN-alpha-treated animals developed antibodies to IFN-alpha that were neutralizing, specific for human recombinant IFN-alpha, and dose dependent in magnitude. The results of this study indicate that human recombinant IFN-alpha is effective in reducing circulating virus antigenic load in cats persistently infected with FeLV-FAIDS. However, the continued efficacy of IFN-alpha therapy appeared to be limited by the formation of cytokine-specific neutralizing antibodies.