Objective-To determine whether FIV infection in captive African lions is associated with changes in immune cell variables similar to those detected in domestic cats infected with FIV. Animals-5 captive African lions naturally infected with FIV (FIV+ and 5 lions not infected with FIV (FIV-). Procedure-Peripheral blood samples were collected from FIV lions during annual examinations conducted during a 7-year period and at a single time point from the FIV- lions. From results of CBC and flow cytometry, lymphocyte subsets were characterized and compared. Results-Flow cytometric analysis revealed that the percentage and absolute number of CD4(+) and CD8(+) T cells were significantly lower in FIV+ lions, compared with these values in FIV- lions. In FIV+ lions, severe depletion in the absolute number of CD4(+) and CD8(+) T cells was detected, although this did not correlate with clinical signs. Muscle wasting was the most consistent clinical sign of infection. Conclusions and Clinical Relevance-Results suggest that FIV+ African lions develop lymphocyte deficiencies, including significant decreases in the absolute number of CD4(+) and CD8(+)T cells; these findings of immune dysfunction are similar to those defined for FIV+ domestic cats. It is important to monitor the number of CD4(+)T cells in infected animals as a measure of disease progression.