Using ex vivo antigen-specific T-cell analysis, we found that symptomatic cytomegalovirus recrudescence in transplant recipients was coincident with reduced expression of gamma interferon (IFN-γ) by virus-specific CD8⁺ T cells and an up-regulation of CD38 expression on these T cells, although there was no significant change in the absolute number of virus-specific cells (as assessed by major histocompatibility complex-peptide multimers). In contrast, HLA class I-matched transplant patients with asymptomatic viral recrudescence showed increased expansion of antigen-specific T cells and highly stable IFN-γ expression by epitope-specific T cells. These studies suggest that a strong functional T-cell response plays a crucial role in defining the clinical outcome of acute viral recrudescence.