To review available drug-resistance patterns of HIV proteinase inhibitors, in particular saquinavir (formerly known as Ro 31-8959), focusing on the implications for disease management. Reduced sensitivity to saquinavir appears to develop slowly and at low frequency even during prolonged therapy, with an incidence of approximately 45% in 1 year of monotherapy. This reduced sensitivity is consistently associated with the presence of two independent mutations in the proteinase gene, glycine-->valine at position 48 and leucine-->methionine at position 90, with the latter predominating in vivo. Double mutants are rare, with a reported incidence of approximately 2% to date. There is no evidence that the incidence of resistance to saquinavir is increased at doses two to four times higher than those used in clinical studies. In fact, the opposite may be true. The incidence of zidovudine resistance is decreased during combination therapy with saquinavir compared to that during monotherapy, while the incidence of resistance to saquinavir is decreased by combination with zidovudine and zalcitabine. CROSS-RESISTANCE: According to the available genotype data, treatment with saquinavir is not associated with mutations at codons 46, 63 and 82, which are reported to induce cross-resistance to many other proteinase inhibitors. Saquinavir may be associated with mutations at position 84, but very rarely. Saquinavir appears to be well-suited to first-line monotherapy or combination therapy without prejudicing subsequent or concurrent use of other proteinase inhibitors not affected by mutations at codons 48 and 90.