HIV-1 viral encephalitis produced by antiretroviral-resistant strains in cerebrospinal fluid (CSF), despite suppression of plasma HIV-1 RNA, has been rarely described. We report two cases of symptomatic viral encephalitis demonstrated by clinical, magnetic resonance imaging (MRI), and an inflammatory CSF profile. Viral load in CSF was 24,000 and 6850 copies/ml, whereas plasma HIV RNA level was undetectable since the beginning of therapy. A resistance test in CSF showed genotypic mutations confering resistance to the drugs the patients received for more than 2 years. In the two cases, a high baseline HIV RNA level, a low nadir CD4(+) count, and suboptimal CSF levels of atazanavir were considered as the risk factors for developing encephalitis. The two cases did not resolve with a change to antiretroviral drugs with better CNS penetration, but they had complete clinical and MRI recovery after changing to therapy considering both CNS viral resistance and penetration.