The aim of this study was to evaluate the prognostic value of changes in CD4 counts and human immunodeficiency virus (HIV) RNA following 6 months of highly active antiretroviral therapy (HAART) in chronic HIV-1 infection. 148 treatment-naive patients treated with 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs) + at least 1 protease inhibitor or non-NRTI for at least 180 d were included. Mean follow-up time after 6 months on HAART was 758 d. The patients were divided into 2 groups based on the increase in CD4 count (deltaCD4) from therapy initiation: groups A (n = 37, deltaCD4 < 0.052 x 10(9)/l) and B (n = 111, deltaCD4 > or = 0.052 x 10(9)/l). Patients were also stratified according to achievement of HIV RNA < 400 copies/ml (n = 122) or > or = 400 copies/ml (n = 26). Endpoints were the occurrence of subsequent HIV-related disease (CDC category B or C) or death after 6 months on HAART. Subjects in group A had an increased risk of HIV-related disease compared with group B when adjusted for CD4 count at initiation of therapy [adjusted risk ratio (RR) 2.62, 95% confidence interval (95% CI) 1.07-6.40]. Viral load > or = copies/ml versus reaching viral suppression < 400 copies/ml was associated with an increased risk of HIV-related disease only in patients with deltaCD4 < 0.052 x 10(9)/l (RR 4.20, 95% CI 1.05-16.9). Thus, this study indicates that patients with no or a small increase in CD4 counts after 6 months of HAART and low CD4 levels at initiation of therapy have an increased risk of HIV-related disease.