CD4⁺ T cells from patients with human immunodeficiency virus (HIV) infection undergo apoptosis at an increased rate, which leads to their depletion during disease progression. Both the Fas-Receptor (Fas-R) and interleukin-1β (IL-1β)–converting enzyme (ICE; caspase 1) appear to play a role in the mechanism of apoptosis of CD4⁺ lymphocytes. Although Fas-R is upregulated on both CD4⁺ and CD8⁺ cells in HIV-infected patients, results from our laboratory and others indicate that, in patients with advanced disease, CD4⁺ cells preferentially express ICE. Protease inhibitors have successfully halted the progression of HIV disease and increased CD4⁺ T counts. In this study, we examined the effect of protease inhibitors on Fas-R (CD95), ICE (caspase 1) expression, apoptosis, and cell death in CD4⁺ T cells of (1) HIV-infected patients who were receiving protease inhibitors, and (2) normal and patient CD4⁺ T cells cultured with a protease inhibitor in vitro. Fifteen patients with advanced HIV disease on treatment showed dramatically decreased CD4⁺ T-cell ICE expression, diminished apoptosis, and increased numbers of CD4⁺ cells within 6 weeks of institution of protease inhibitor therapy, and before down-modulation of Fas-R (CD95) expression was evident. To determine the role of HIV infection, we studied the effect of ritonavir, a protease inhibitor, on normal and patient cells in vitro. Stimulated and unstimulated normal CD4⁺ T cells, cultured with protease inhibitor, demonstrated markedly decreased apoptosis and ICE expression (P = .01). While Fas-R expression was not significantly altered during short-term culture by such treatment, Fas-Ligand (Fas-L) membrane expression of phytohemagglutinin (PHA)-stimulated blood lymphocytes was decreased by protease inhibitor. In the presence of ritonavir, CD4⁺ T cells from HIV-infected patients showed similar changes in ICE intracellular levels without alteration of Fas expression. In conclusion, protease inhibitors appear to decrease CD4⁺ T-cell ICE expression and apoptosis before they affect Fas-R expression in HIV-infected patients. This action was independent of HIV infection, as similar effects were seen in CD4⁺ T cells from normal controls. Some of the benefit of protease inhibitors may be related to modification of programmed cell death, which increases CD4⁺ T-cell number. Whether this is due to directly to the changes effected in the caspase system remains to be determined.