The effect of interleukin-2 (IL-2) on the plasma levels of hepatitis C RNA (HCV-RNA) has varied in published reports. We measured the impact of IL-2 on plasma HCV RNA levels in 54 human immunodeficiency virus (HIV)/HCV coinfected patients enrolled in a randomized trial of 512 participants designed to compare the virologic and immunologic effects of cycled IL-2 plus antiretroviral therapy (ART) vs ART alone in the treatment of HIV in patients with CD4 cell counts > or =300 cells/mm(3). The mean decreases in average HCV RNA levels (copies/mL, log (10)) were 0.28 log in the IL-2 group (n = 26) and 0.04 log in the ART alone group (n = 28) at 12 months (P = 0.18). The changes in HCV RNA level were not associated with baseline or nadir CD4 cell counts, baseline aspartate aminotransferanse, CD4 cell response to IL-2, or changes in plasma HIV RNA values. Compared with those participants who only had HIV, the HIV/HCV co-infected patients did not have a significantly different CD4 cell response to IL-2 therapy. Intermittent IL-2 therapy does not produce a significant sustained decrease in plasma HCV RNA levels among patients co-infected with HIV/HCV who are on highly active ART.