OBJECTIVE To assess the clinical, immunological and virological response and the emergence of resistance towards antiretroviral therapy (ART) in a cohort of HIV-2-infected patients. METHODS Observational study. METHODS HIV-2-infected patients residing in the Netherlands. RESULTS From 1995 to 2001 seven patients failed various ART regimens. The resistance mutations were analysed retrospectively. Development of mutations proved to be similar to that observed in HIV-1-infected patients, with the exception of a higher occurrence of the Q151M mutation within the reverse transcriptase gene. In a prospective study, comprising 13 consecutive naive HIV-2-infected patients, all patients achieved plasma HIV-2-RNA suppression below the detection limit (500 copies/ml). The antiretroviral regimen consisted of two nucleoside reverse transcriptase inhibitors (NRTIs) and indinavir, with a boosting dose of ritonavir; the median follow-up was 91 weeks. Two patients experienced a temporary virological rebound, while at the same time therapeutic drug monitoring showed sub-therapeutic plasma levels of indinavir. CONCLUSIONS Sustained viral suppression in HIV-2-infected patients can be achieved using an antiretroviral regimen of two NRTIs and boosted indinavir or lopinavir.