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Most patients with human immunodeficiency virus (HIV) who remain CD4+ T-cell deficient on antiretroviral therapy (ART) exhibit marked immune activation. As CD4+ T-cell activation may be mediated by microbial translocation or interferon-alpha (IFN-α), we examined these factors in HIV patients with good or poor CD4+ T-cell recovery on long-term ART. Messenger RNA levels for 3 interferon-stimulated genes were increased in CD4+ T cells of patients with poor CD4+ T-cell recovery, whereas levels in patients with good recovery did not differ from those in healthy controls. Poor CD4+ T-cell recovery was also associated with CD4+ T-cell expression of markers of activation, senescence, and apoptosis, and with increased serum levels of the lipopolysaccharide receptor and soluble CD14, but these were not significantly correlated with expression of the interferon-stimulated genes. Therefore, CD4+ T-cell recovery may be adversely affected by the effects of IFN-α, which may be amenable to therapeutic intervention.