BACKGROUND: Cytomegalovirus (CMV) remains an important pathogen in solid organ transplantation, particularly lung transplantation. Lung transplant recipients (LTRs) mismatched for CMV (donor positive/recipient negative [D(+)R(-)]) are at highest risk for active CMV infection and have increased mortality. However, the correlates of immune control during chronic CMV infection remain incompletely understood. METHODS: We prospectively studied 22 D(+)R(-) LTRs during primary CMV infection and into chronic infection. Immune responses during primary infection were analyzed for association with viral relapse during early chronic infection. RESULTS: Primary CMV infection was characterized by a striking induction of T-box transcription factor (T-bet) in CD8(+) T cells. CMV-specific effector CD8(+) T cells were found to be T-bet(+). After primary infection, 7 LTRs lacked immune control with relapsing viremia during early chronic infection. LTRs with relapsing viremia had poor induction of T-bet and low frequencies of phosphoprotein 65 (pp65)-specific CD8(+) effector T cells during primary infection. However, frequencies of IE1-specific CD8(+) effector T cells during primary infection were not associated with early relapsing viremia. CONCLUSIONS: T-bet plays an important role in coordinating CD8(+) effector responses to CMV during primary infection. Moreover, CD8(+) T-bet induction and pp65-specific CD8(+) effector responses at the time of primary infection are important predictors of immune control of CMV during early chronic infection.