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To determine the long-term T-lymphocyte response to highly active antiretroviral therapy (HAART) and to define predictors of the immunological response.Cohort study, including 135 HIV-1-infected subjects at a city general practice who commenced HAART between 1996 and 1998.Collection of plasma HIV-1 RNA, CD4+ and CD8+ T-lymphocyte data at 3-6 monthly time intervals over 2 years.Seventy-three subjects (54%) achieved suppression of plasma HIV-1 RNA to levels below 400 copies/ml during the observation period, 31 individuals (23%) had detectable plasma HIV-1 RNA below 10 000 copies/ml and 31 subjects (23%) had virological failures with viral loads above 10 000 copies/mL. Median CD4+ T lymphocytes increased from 246 to 463 × 106 cells/l , showing a median rise of 20 × 106 cells/l per month in the first 3 months and 7 × 106 cells/l per month thereafter. The proportion of individuals who reached CD4+ cell counts above 500 × 106 cells/l increased from 8% at baseline to 54% at 2 years. Treatment-naïve individuals, subjects with a large reduction of HIV-1 RNA or a large early CD8+ increase had better early CD4+ responses. Long-term CD4+ T-cell increases were inversely correlated with mean plasma HIV-1 RNA levels. Baseline CD4+ T-cell count was the most important determinant of reaching CD4+ cell counts above 500 × 106 cells/l. Nineteen per cent of subjects had no further CD4+ T-cell increases in the second year of therapy despite undetectable viral load.Immune reconstitution is a slow process, showing a large individual variability. The virological response to HAART was the most important determinant of the immunological short- and long-term response.