This study evaluated 1433 human immunodeficiency virus (HIV)-infected patients starting highly active antiretroviral therapy (HAART), 409 (28%) of whom had prior nucleoside experience and achieved an HIV load of <400 copies/mL by 24 weeks of therapy. Three hundred seven patients experienced virus rebound during a total of 2773.3 person-years of follow-up. There was a higher rate of virus rebound among the patients with pre-HAART nucleoside experience (relative hazard [RH], 2.86; 95% confidence interval, 2.22-3.84; P<.0001) and a decreasing rate of virus rebound with increasing duration of virus suppression (i.e., time since achieving a virus load of <400 HIV RNA copies/mL) among both the nucleoside-experienced and naive patients (P<.0001), but the difference between the groups persisted into the third year of follow-up (P=.0007). Even patients who had experienced <2 months of nucleoside therapy before beginning HAART had an increased risk of virus rebound (RH, 1.95; P=.009). It appears that only a small period of pre-HAART nucleoside therapy is sufficient to confer a disadvantage, in terms of risk of virus rebound, that persists for several years.