BACKGROUND: Although antiretroviral therapy has the ability to fully restore a normal CD4(+) cell count (>500 cells/mm(3)) in most patients, it is not yet clear whether all patients can achieve normalization of their CD4(+) cell count, in part because no study has followed up patients for >7 years. METHODS: Three hundred sixty-six patients from 5 clinical cohorts who maintained a plasma human immunodeficiency virus (HIV) RNA level 1000 copies/mL for at least 4 years after initiation of antiretroviral therapy were included. Changes in CD4(+) cell count were evaluated using mixed-effects modeling, spline-smoothing regression, and Kaplan-Meier techniques. RESULTS: The majority (83%) of the patients were men. The median CD4(+) cell count at the time of therapy initiation was 201 cells/mm(3) (interquartile range, 72-344 cells/mm(3)), and the median age was 47 years. The median follow-up period was 7.5 years (interquartile range, 5.5-9.7 years). CD4(+) cell counts continued to increase throughout the follow-up period, albeit slowly after year 4. Although almost all patients (95%) who started therapy with a CD4(+) cell count 300 cells/mm(3) were able to attain a CD4(+) cell count 500 cells/mm(3), 44% of patients who started therapy with a CD4(+) cell count <100 cells/mm(3) and 25% of patients who started therapy with a CD4(+) cell count of 100-200 cells/mm(3) were unable to achieve a CD4(+) cell count >500 cells/mm(3) over a mean duration of follow-up of 7.5 years; many did not reach this threshold by year 10. Twenty-four percent of individuals with a CD4(+) cell count <500 cells/mm(3) at year 4 had evidence of a CD4(+) cell count plateau after year 4. The frequency of detectable viremia ("blips") after year 4 was not associated with the magnitude of the CD4(+) cell count change. CONCLUSIONS: A substantial proportion of patients who delay therapy until their CD4(+) cell count decreases to <200 cells/mm(3) do not achieve a normal CD4(+) cell count, even after a decade of otherwise effective antiretroviral therapy. Although the majority of patients have evidence of slow increases in their CD4(+) cell count over time, many do not. These individuals may have an elevated risk of non-AIDS-related morbidity and mortality.