The main goal of this study was to assess the role of mycophenolate mofetil (MMF) during interruption of highly active antiretroviral therapy (HAART). Seventeen patients with early-stage chronic HIV type 1 infection were treated with HAART for 12 months. They were then randomized (day 0) to receive MMF (HAART–MMF group, n = 9) or to continue the regimen (HAART group, n = 6) for 120 additional days. At day 120 in the HAART–MMF group, HAART was discontinued, and MMF administration was continued. The primary end point of the study was the number of individuals maintaining a plasma viral load (VL) set point of <200 copies/mL after at least 6 months off HAART. At day 120, all patients in both groups had undetectable plasma VLs. After 6 months off HAART, 5 of 9 patients in the HAART–MMF group versus 1 of 6 patients in the HAART group maintained a plasma VL of <200 copies/mL (P = 0.28). According to the ability of their plasma to inhibit cellular proliferation, patients were reclassified and divided into an inhibition group (n = 6) and a no inhibition group (n = 9). The doubling time of VL rebound was significantly higher in the inhibition group (mean ± SE, 10.22 ± 1.3) than in the no inhibition group (mean ± SE, 4.6 ± 1.6; P = 0.03). Moreover, 5 of 6 patients in the inhibition group maintained a plasma VL of <200 copies/mL versus 1 of 9 patients in the no inhibition group (P = 0.005) after 6 months off HAART. We found that combining MMF and HAART delayed VL rebound and improved control of viral replication without HAART but only when inhibition of lymphocyte proliferation was achieved.