As ritonavir (Norvir) is now rarely given as the only protease inhibitor in an anti-HIV treatment regimen, ritonavir resistance rarely develops. However, previous studies have found that mutations in the protease gene at codons 82 and 84 are associated with resistance to ritonavir, as well as mutations M46I/L, I50V, I54V and L90M. The I84V mutation reduces susceptibility to all available protease inhibitors, whereas V82A/T/F/S reduces susceptibility to indinavir and lopinavir.

HIV that is resistant to ritonavir is usually entirely cross-resistant to indinavir (Crixivan), and tends to reduce responses to nelfinavir (Viracept) and saquinavir (Invirase) tend to be poor.