Information about the efficacy of antiretroviral drugs in HIV-1 group O strains as well on the virus evolution in terms of resistance development in vivo is very limited. We assessed the clinical, immunological, and virological response to antiretroviral therapy as well as the selection of drug resistance in six HIV-1 group O-infected patients. All but one initiated antiretroviral therapy with two nucleoside reverse transcriptase inhibitors (NRTI) plus one protease inhibitor (PI). At baseline, median plasma HIV-1 group O RNA and CD4 counts were 32,256 (15,770-74,132) copies/ml and 88 cells/microl (13-170), respectively. Four patients reached undetectable plasma viremia 12 weeks after beginning treatment. However, viremia rebounded in one of them due to poor compliance. Another two patients had an initial reduction in plasma HIV-RNA greater than 1 log, but rebounded soon thereafter. At baseline, all patients' viruses revealed changes associated with NNRTI resistance (98G and 181C). Two out of three patients failing therapy developed resistance mutations. One selected changes M41L, E44D, D67N, V75M, M184V, and T215Y at the RT, and G48M, F53L, I54V, V82A, and L90M at the protease. Another selected mutations K70N, V75A, and M184V at the RT, and D30D/N and I84V at the protease while failing on indinavir. Interestingly, both patients showed a shift at codon 181 from C to Y, which might restore NNRTI susceptibility. Sustained viral suppression in HIV-1 group O-infected patients can be successfully achieved using antiretroviral regimens based on two NRTI and a boosted PI. Drug resistance mutations in HIV-1 group O seem to be selected at similar positions to those in HIV-1 group M viruses.