Many post-exposure prophylaxis guidelines recommend triple drug combinations containing protease inhibitors after occupational and non-occupational HIV exposure. Although ritonavir-boosted lopinavir (Kaletra) is commonly recommended, most protease inhibitors can be used safely. However, indinavir (Crixivan) has fallen out of favour as it is poorly tolerated.

Unlike non-nucleoside reverse transcriptase inhibitors (NNRTIs), the protease inhibitors tend to have less serious side-effects, although many patients do suffer from nausea, vomiting and diarrhoea. Nelfinavir (Viracept) is noted in some PEP guidelines as frequently causing diarrhoea in people taking PEP.