Saquinavir (SQV) is a protease inhibitor that binds to the protease active site of the human immunodeficiency virus and prevents the cleavage of viral polyproteins resulting in the formation of non-infectious virus particles. The purpose of these studies was to determine the potential effects of SQV on the immune system in female B₆C₃F₁ mice. SQV was administered by gavage twice daily for 28 days at total doses of 300, 600, and 1200 mg/kg/day. No significant differences were observed in body weight, or the weights of spleen, thymus, liver, kidneys, or lungs. Exposure to SQV produced no biologically meaningful changes in hematological parameters. However, a statistically significant increase in the number of T-cells (23%) was observed at the high dose level of SQV. The number of splenic immature T-cells (CD4+CD8+ cells) also showed increases of 46% and 92% at the 600 and 1200 mg/kg dose levels, respectively. The immunoglobulin M antibody-forming cell (AFC) response was significantly increased by 41% when the data were expressed as AFC/10⁶ spleen cells at the 1200 mg/kg dose level. Treatment with SQV had no effects on the mixed leukocyte response. Overall, the activities of natural killer cells and cytotoxic T-cells were not altered in SQV-treated animals when compared to vehicle controls. In addition, exposure to SQV did not affect host resistance in the B16F10 melanoma model. In conclusion, SQV produced an enhancement of the humoral immune response, possibly through modulating T-cell function in female B₆C₃F₁ mice.