OBJECTIVE To review drug-resistance patterns of HIV protease inhibitors, with particular reference to saquinavir, and how resistance and cross-resistance patterns may influence disease management. Resistance to saquinavir in vitro and in vivo is associated with mutations L90M and G48V in HIV protease. L90M is the predominant mutation in vivo. Clinically, G48V is uncommon and the double mutation rare. This pattern of mutation differs from those seen with other protease inhibitors. CROSS-RESISTANCE: Long-term treatment with saquinavir in most cases does not induce a significant decrease in sensitivity to saquinavir itself or other protease inhibitors. Where significant resistance to saquinavir does develop (i.e. fourfold increase in the median inhibitory concentration), there are observed instances of cross-resistance. Preliminary phenotypic studies of patients on combination therapy with saquinavir (plus zalcitabine and/or zidovudine) for 1 year indicate that > 80% should subsequently respond to indinavir, ritonavir or VX-478. CONCLUSIONS Resistance to saquinavir develops slowly and in a minority of patients on long-term therapy. Reduced susceptibility to saquinavir is associated with mutations different from those associated with other HIV protease inhibitors. Saquinavir appears to be a good first-choice protease inhibitor for combination therapy with HIV reverse transcriptase inhibitors as it should provide prolonged antiretroviral activity without limiting subsequent therapeutic options.