OBJECTIVE: Characterize responses to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral treatment (ART) initiated during acute HIV infection (AHI). DESIGN: This was a prospective, single-arm evaluation of once-daily, co-formulated emtricitabine/tenofovir/efavirenz initiated during AHI. METHODS: The primary endpoint is the proportion of responders with HIV RNA less than 200 copies/ml by week 24. We examined time to viral suppression and CD8 cell activation in relation to baseline participant characteristics. We compared time to viral suppression and viral dynamics using linear mixed-effects models between acutely infected participants and chronically infected controls. RESULTS: Between January 2005 and May 2009, 61 AHI participants were enrolled. Of participants whose enrollment date allowed 24 and 48 weeks of follow-up, 47 of 51 (92%) achieved viral suppression to less than 200 copies/ml by week 24, and 35 of 41 (85.4%) to less than 50 copies/ml by week 48. The median time from ART initiation to suppression below 50 copies/ml was 93 days (range 14-337). Higher HIV RNA levels at ART initiation (P = 0.02), but not time from estimated date of infection to ART initiation (P = 0.86), were associated with longer time to viral suppression. The median baseline frequency of activated CD8+CD38+HLA-DR+ T cells was 67% (range 40-95), and was not significantly associated with longer time to viral load suppression (P = 0.15). Viremia declined to less than 50 copies/ml more rapidly in AHI than chronically infected participants. Mixed-model analysis demonstrated similar phase I HIV RNA decay rates between acute and chronically infected participants, and more rapid viral decline in acutely infected participants in phase II. CONCLUSION: Once-daily emtricitabine/tenofovir/efavirenz initiated during AHI achieves rapid and sustained HIV suppression during this highly infectious period.