To evaluate the frequency and predictive factors of discordant immune response, we performed a prospective cohort study of 288 antiretroviral-naive human immunodeficiency virus (HIV)-infected patients who initiated highly active antiretroviral therapy (HAART) and maintained complete virus suppression for > or =24 months. The median CD4+ cell count was 186x10(6) cells/L, and the median HIV RNA level was 5 log(10) copies/mL. After 24 months of therapy, 42 (16.5%) of 255 patients had a median CD4+ cell count increase of <100x10(6) cells/L. By logistic regression analysis, previous injection drug use was associated with a CD4+ cell count increase of <100x10(6) cells/L (risk ratio [RR], 2.326; 95% confidence interval [CI], 1.077-5.023; P=.032); inclusion of a protease inhibitor (PI) in the HAART regimen reduced the risk of poor immunologic recovery (RR, 0.160; 95% CI, 0.061-0.417; P<.001). Failure of the CD4+ cell count to increase was relatively common among antiretroviral-naive patients in the year after the initiation of HAART and the achievement of complete virus suppression. PI-containing regimens provided better immunologic response.