Highly active antiretroviral therapies (HAARTs) that contain human immunodeficiency virus (HIV) protease inhibitors (PIs) or nonnucleoside reverse-transcriptase inhibitors (NNRTIs) were compared for their effect on secretory aspartyl proteinase (Sap), a virulence trait for mucosal candidiasis. In therapy-naive HIV-positive subjects, oral Sap was detected in 11, 6, 3, 0, and 0 of 15 subjects treated with PI-HAART and in 7, 7, 9, 6, and 5 of 15 subjects treated with NNRTI-HAART, on days 0, 14, 30, 90, and 180 of treatment, respectively. In another 30 subjects, Sap was detected in 0 and 7 of 15 subjects after 1 year of treatment with PI-HAART or NNRTI-HAART, respectively. The anti-Sap effect of PI-HAART was associated with clinical resolution of oral candidiasis but not with late and inconstant recovery of anticandidal cellular immunity. In all subjects, the 2 therapeutic regimens compared well in increasing CD4(+) cell count and abating viremia. Thus, PIs exert an early, immune reconstitution-independent effect on Candida virulence in the oral cavities of HIV-positive subjects.