Background: Interleukin 2 (IL-2) administration increases CD4 counts in persons with higher counts. This study investigated persons with moderately advanced human immunodeficiency virus infection receiving highly active antiretroviral therapy (HAART). Methods: Two hundred four patients with CD4 T-cell counts from 50/μL to 350/μL who were treatment naive or had been treated only with reverse transcriptase inhibitors began a specified protease inhibitor HAART regimen. Virologic responders (≤5000 copies/mL) at 12 weeks were randomized to open-label continuous-infusion IL-2 (IV IL-2), subcutaneous IL-2 (SC IL-2), or HAART alone. Thirty were not randomized and 15 enrolled in a substudy, leaving 159 for analysis. Subjects continued HAART alone for 72 weeks (n=52) or with IV IL-2 (n=53) or SC IL-2 (n=54) for 5 days every 8 weeks. The IV IL-2 subjects could switch to SC IL-2 if their CD4 T-cell count increased by 100/μL or by 25%. Results: Patients receiving IV or SC IL-2 had greater increases in CD4 cell counts. At week 84, median increases were 459/μL, 312/μL, and 102/μL. Increases of greater than 50% at week 60 (primary end point) were achieved in 39 patients (81%) and 32 (67%) in the IV and SC IL-2 arms, respectively, compared with 13 (29%) in the HAART arm (P<.001 for both). Treatment with IL-2 did not increase plasma human immunodeficiency virus RNA levels. There were fewer new AIDS-defining events in the IV (P=.006) and SC (P=.03) IL-2 groups than in the HAART group (0, 1, and 7, respectively). Drug-related adverse events were more frequent with IL-2 treatment. Conclusion: Addition of IL-2 to HAART can significantly expand CD4 T-cell counts in moderately advanced human immunodeficiency virus infection, without loss of virologic control. ©2007 American Medical Association. All rights reserved.