Feline immunodeficiency virus sustains an AIDS-like syndrome in cats, which is considered a relevant model for human AIDS. Under precise enrolment requirements, 30 naturally infected cats showing overt disease were included in a trial of low-dose, oral human interferon-alpha treatment. Twenty-four of them received 10 IU/Kg of human interferon-alpha and 6 placebo only on a daily basis under veterinary supervision. The low-dose human interferon-alpha treatment significantly prolonged the survival of virus-infected cats (p<0.01) and brought to a rapid improvement of disease conditions in the infected hosts. Amelioration of clinical conditions was neither correlated with plasma viremia, nor with proviral load in leukocytes. A good survival of CD4+ T cells and a slow increase of CD8+ T cells were also observed in human interferon-alpha-treated cats. Interestingly, the improvement of the total leukocyte counts showed a much stronger correlation with the recovery from serious opportunistic infections. As shown in other models of low-dose interferon-alpha treatment, there was a rapid regression of overt immunopathological conditions in virus-infected cats. This hints at a major role of interferon-alpha in the control circuits of inflammatory cytokines, which was probably the very foundation of the improved clinical score and survival despite the unabated persistence of virus and virus-infected cells.