Thymus involvement and the development of thymic lesions in HIV-1 infection is hypothesized to suppress thymus function and limit T cell maturation and replenishment of the peripheral lymphoid pool. Therapeutic modulation to protect or enhance thymus function may therefore ameliorate peripheral lymphocytopenia and retard disease progression. Thymotrophic agents, such as insulin-like growth factor type I (IGF-I), may therefore represent adjunctive but important methods of treatment to protect or promote thymus function. The assessment of rhIGF-I in lentiviral infection and its impact on the thymus was performed using the feline immunodeficiency virus (FIV) model. Regeneration of the thymus in juvenile cats and amelioration of the thymic lesion after FIV infection was assessed by multiple measurements including thymic weight, stereologic analysis of the thymus cortex and medulla, histologic and immunohistologic analysis, quantitation of thymocyte and peripheral lymphocyte subsets, and quantitative competitive RT-PCR. Evidence of thymic cortical regeneration was observed in FIV-inoculated cats after 12 and 20 weeks of rhIGF-I treatment. Inflammation in the thymus was reduced during this period of treatment in this group of rhIGF-I/FIV-inoculated cats as evidenced by the reduced numbers of B cells detected. Viral replication rates in peripheral lymph nodes were not altered by rhIGF-I treatment and were decreased by 1 log in the thymus after 20 weeks of treatment. Peripheral blood CD4+ T cell counts also increased after 14 weeks of treatment. This suggests that rhIGF-I treatment can enhance thymus function and replenishment of the peripheral T cell pool.