Protease inhibitors used in combination with reverse transcriptase inhibitors have demonstrated potent anti-HIV-1 activity in vitro as well as in vivo. We evaluated interactions among five protease inhibitors: indinavir (IDV), ritonavir (RTV), saquinavir (SQV), amprenavir (APV), and nelfinavir (NFV), when used in combinations of two and three drugs in vitro against several HIV-1 isolates, including those susceptible and resistant to various nucleoside and nonnucleoside reverse transcriptase inhibitors. Interactions ranged from synergy to slight antagonism depending on the viral isolates and the experimental conditions employed. Further clinical evaluation of protease inhibitor combinations is warranted.