The role of autochthonous peritoneal feline macrophages (Mθ) in the age-related resistance of cats to feline leukemia virus (FeLV) was investigated by a study of the functional properties and FeLV susceptibility of Mθ from kittens and adult cats and the effect of hydrocortisone (HC) and silica on Mθ-FeLV interactions. Although the phagocytic functions of isolated Mθ from kittens and adults were equivalent, the mean FeLV susceptibility of Mθ from kittens was five times that of Mθ from adult cats, thus establishing a direct correlation between the age-related susceptibility of cats and Mθ from cats to FeLV. Mθ of viremic cats were found to be infected with FeLV in vivo; virus titers were slightly higher than those obtained after in vitro infection of Mθ. Mθ from cats that had experienced regressive FeLV infection were not significantly more resistant to FeLV infection in vitro than were Mθ from naive adult specific-pathogen-free cats. HC, which has been shown to enhance the in vivo FeLV susceptibility of cats, also enhanced the permissiveness of Mθ from cats to FeLV in vitro (600-fold for Mθ from adult cats and 200-fold for Mθ) from kittens. Mθ permissiveness to FeLV was highly sensitive to HC and occurred in Mθ infected in vivo or in vitro. In parallel with the effect of HC on the natural resistance of cats to FeLV, administration of silica before virus inoculation also markedly enhanced the FeLV susceptibility of adult cats. Silica was toxic for isolated Mθ but not for lymphocytes in vitro, and silica produced monocytopenia and neutrophilia, delayed skin allograft rejection, and augmented feline oncovirus-associated cell membrane antigen antibody responses in vivo. These experiments indicate that Mθ were linked to the natural resistance of cats to FeLV and that the temporary elimination of Mθ functions (e.g., by silica) and/or the conversion of the Mθ-FeLV relationship from a nonpermissive to a permissive state (e.g., by corticosteroids) resulted in failure of early virus containment, in persistent virus amplification in hemolymphatic tissues, and in subsequent FeLV-related proliferative or antiproliferative disease.