Plasma levels of cytomegalovirus (CMV)-specific immunoglobulin G (IgG), soluble (s) CD30, sCD26 (dipeptidyl peptidase IV [DPP IV]) enzyme activity, and tumor necrosis factor receptor-I (TNFR-I) were assessed in human immunodeficiency virus (HIV)-infected patients who experienced CMV retinitis (CMVR) as an immune restoration disease (IRD) during their first 6 months of highly active antiretroviral therapy (HAART) and in CMV-seropositive, HIV-infected patients with similar baseline CD4(+) T cell counts who had uneventful immune reconstitution. Patients who experienced CMVR IRD had a significant increase in CMV-specific IgG during their first 12 months of HAART, indicating restored CMV-specific immune responses. They also had significantly higher levels of sCD30 both before HAART and for up to 12 months after start of treatment. sCD30 levels remained elevated during 48 months of HAART, suggesting persistence of a predominant Th2 cytokine environment. Levels of sCD26 (DPP IV) enzyme activity and TNFR-I did not differ significantly between the 2 groups at any time point.