Effects of a human immunodeficiency virus (HIV) type 1 protease inhibitor, ritonavir, were evaluated in 21 patients enrolled in a phase I/II study. The magnitude and rates of CD4 and CD8 lymphocyte increase, changes in subsets of CD4 and CD8 lymphocytes, and proliferative responses to mitogen and antigens were analyzed. Significant increases were noted in CD4 and CD8 lymphocyte counts; numbers of CD4CD45RO lymphocytes increased significantly by week 1 of therapy. Increases in the CD4CD45RA subset were observed at week 4. Reductions in the percentage of CD4 and CD8 lymphocytes expressing CD38 were noted. Increases in proliferative responses to phytohemagglutinin were noted in 6 of 7 patients and correlated with duration of virus load suppression. Increased responses to recall antigens and to HIV-specific proteins were observed. Treatment with ritonavir produced alterations in the immune system that included changes in T cell subset distribution and increases in CD4 and CD8 lymphocyte numbers and of lymphocyte function.