The overall value of initiating anti-retroviral therapy during the acute phase of human immunodeficiency virus type 1 (HIV-1) infection remains unclear. From a clinical perspective, the lack of data from controlled randomized clinical trials limits understanding of long-term effects of treatment on the clinical course of HIV infection. Based on available data, the impact of anti-retroviral therapy during acute infection on the immune response against HIV-1 is not particularly encouraging. Recent observations on the very early depletion of lymphocyte reservoirs in the gastrointestinal tract may partially explain the limited benefit of anti-retroviral therapy initiated during the acute phase of HIV-1 infection. This may also help to explain the dichotomy between early observations demonstrating apparent immunological benefit with early anti-retroviral treatment that were associated none the less with inability to control viral replication following treatment interruption.