BACKGROUND A CD8+ T-cell response to cytomegalovirus (CMV) has been associated with control of viral replication. Assessment shortly after the onset of asymptomatic viremia could help significantly refine preemptive strategies. METHODS We conducted a prospective study of organ transplant recipients who developed asymptomatic low-level viremia not initially requiring antiviral therapy. Cell-mediated immunity (CMI) was measured shortly after viremia onset and longitudinally using the Quantiferon-CMV assay. The primary outcome was the ability to predict spontaneous clearance versus virologic and/or clinical progression. RESULTS We enrolled 42 transplant patients, of which 37 were evaluable. Viral load at onset was 1140 copies/mL (interquartile range 655-1542). Spontaneous viral clearance occurred in 29 of 37 (78.4%) patients and 8 of 37(21.6%) had clinical and/or virologic progression requiring antivirals. At baseline, a positive CMI test (interferon-γ≥0.2 IU/mL) was present in 26 of 37(70.3%) patients. In patients with a positive CMI, the incidence of subsequent spontaneous viral clearance was 24 of 26 (92.3%) compared with 5 of 11 (45.5%) in patients with a negative CMI at onset (P=0.004). The absolute interferon-γ production was higher in patients with spontaneous clearance versus progression at all time points tested. Analysis of different cutoffs for defining a positive test suggested that the best threshold was 0.1 or 0.2 IU/mL of interferon-γ. CONCLUSIONS CMI assessment shortly after the onset of CMV viremia may be useful to predict progression versus spontaneous viral clearance, thereby helping guide the need for antiviral therapy and refining current preemptive strategies.