Human immunodeficiency virus type 1 (HIV-1) protease inhibitors are a promising class of antiretroviral agents that compromise enzymatic function through substrate mimicry. The in vitro susceptibility of a panel of HIV-1 clinical isolates demonstrating various drug resistance phenotypes to combinations of the HIV-1 protease inhibitors saquinavir and indinavir was determined. Antiviral effect was assessed by an HIV-1 p24 antigen reduction assay in phytohemagglutinin-stimulated peripheral blood mononuclear cells after harvesting of cell-free supernatant fluids at peak antigen production (days 4-7). Drug interactions were determined by median-dose-effect analysis, with the combination index (CI) calculated at several inhibitory concentrations (IC50, IC75, IC90, IC95, IC99). The interactive effects ranged from synergy at low efficacy doses to antagonism at higher doses against a pan-susceptible clinical isolate of HIV-1. Against a zidovudine-resistant isolate as well as a multidrug-resistant isolate, the combination of saquinavir and indinavir demonstrated antagonism at all doses.