Abstract OBJECTIVE: The aim of the study was to analyse the response to highly active antiretroviral therapy (HAART) initiated at the time of primary HIV infection (PHI) in patients infected with a virus resistant to > or = 1 drug of their treatment compared with patients infected with a wild-type virus. METHODS: We analysed data from 350 patients who were enrolled from 1996-2004 in the French ANRS PRIMO Cohort or in the ANRS Resistance Group and treated with HAART during PHI. During the study period, HAART was initiated before the result of the genotypic resistance test was available. We compared patients infected with a virus resistant to > or = 1 drug of their regimen (GR group, n = 46) with patients harbouring a wild-type virus (WT group, n = 304). Virological and immunological response to treatment according to drug-resistance profile was analysed 3 months and 6 months after HAART initiation. RESULTS: In GR and WT groups, HIV RNA level was < 400 copies/ml in 68% and 83% (P = 0.02) and < 50 copies/ml in 23% and 40% (P = 0.08) 3 months after HAART initiation. In multivariable logistic regression taking into account gender, age, boosted PI regimen, plasma HIV RNA and CD4+ T-cell count at HAART initiation, patients with virus resistant to > or = 1 drug of their regimen were significantly less likely to achieve undetectable viral load at month 3 (odds ratio 0.32, 95% confidence interval 0.15-0.72) than the others. This difference was sustained up to month 6. CONCLUSION: In this large cohort of HAART-treated PHI-patients, the presence of drug resistance mutations led to suboptimal response to early therapy.