Objectives:To identify the predictors of cytomegalovirus reactivation in AIDS patients on highly active antiretroviral therapy (HAART).Design:This prospective study enrolled cytomegalovirus-seropositive AIDS patients on or about to start HAART, who were not receiving anti-cytomegalovirus prophylaxis. Clinical and laboratory data were collected over 3.5 years at clinic visits, which coincided with the study visits.Methods:Blood was obtained at every study visit and was used for measurements of cytomegalovirus cell-mediated immunity (lymphocyte proliferation, IFN-γ, IL-2, and IL-10 production), cytomegalovirus viral load, CD4 cell count, and HIV viral load. A logistic-normal model was used to analyse outcome data with repeated observations.Results:Twenty-six patients had 40 episodes of cytomegalovirus reactivation (positive cytomegalovirus viral load) during the study. Their immunological and virological parameters were compared with 26 randomly selected control individuals from the same cohort. The risk of cytomegalovirus reactivation significantly decreased with every 6-month increase in HAART duration [odds ratio (OR) 0.5;P= 0.02] and marginally increased with every log10RNA copies/ml HIV viral load (OR 2;P= 0.07). CD4 cell counts, cytomegalovirus lymphocyte proliferation, IL-2, and IL-10 did not reach significance as predictors of cytomegalovirus reactivation. However, cytomegalovirus IFN-γ production significantly decreased the risk of cytomegalovirus reactivation (OR 0.03;P= 0.04).Conclusion:Cytomegalovirus-specific IFN-γ has a unique value as an immunological predictor of cytomegalovirus reactivation, demonstrating the importance of cellular immune responses in the control of cytomegalovirus replication in HAART recipients.