Control of viral replication to below the level of quantification using combination antiretroviral therapy (ART) [cART] has led to a dramatic fall in mortality and morbidity from AIDS. However, despite the success of cART, it has become apparent that many patients do not achieve normalized CD4+ T-cell counts despite virological suppression to below the level of quantification (<50 copies/mL). Increasing data from cohort studies and limited data from clinical trials, such as the SMART study, have shown that higher CD4+ T-cell counts are associated with reductions in morbidity and mortality from both AIDS and serious non-AIDS (SNA) conditions, including cardiovascular disease. Enhancement of immune restoration over and above that achievable with ART alone, using a number of strategies including cytokine therapy, has been of interest for many years. The most studied cytokine in this setting is recombinant interleukin (IL)-2 (rIL-2). The purpose of this review is to describe the current status of rIL-2 as a therapeutic agent in the treatment of HIV-1 infection. The review focuses on the rationale underpinning the exploration of rIL-2 in HIV infection, summarizing the phase II and III findings of rIL-2 as an adjunctive therapy to ART and the phase II studies of rIL-2 as an antiretroviral-sparing agent. The phase II studies demonstrated the potential utility of continuous intravenous IL-2 and subsequently intermittent dosing with subcutaneous rIL-2 as a cytokine that could expand the CD4+ T-cell pool in HIV-1-infected patients without any significant detrimental effect on HIV viral load and with an acceptable adverse-effect profile. These data were utilized in designing the phase II studies of rIL-2 as an ART-sparing agent and, more importantly, the large phase III clinical endpoint studies of rIL-2 in HIV-1-infected adults, ESPRIT and SILCAAT. In the latter, subcutaneous rIL-2 was given intermittently (5 days of twice-daily dosing at 4.5-7.5 million international units per dose every 8 weeks) to HIV-1-infected adults receiving cART using an induction/maintenance strategy. Both studies explored the clinical benefit of intermittent subcutaneous rIL-2 with cART versus cART in HIV-infected adults with CD4+ T-cell counts > or = 300 cells/microL (ESPRIT study) and 50-299 cells/microL (SILCAAT study). Both studies showed that receipt of rIL-2 conferred no clinical benefit despite a significantly higher CD4+ T-cell count in the rIL-2 arms of both studies. Moreover, there was an excess of grade 4 clinical events in ESPRIT rIL-2 recipients. The results of the phase III clinical endpoint studies showed that rIL-2 has no place as a therapeutic agent in the treatment of HIV infection.