CMV remains an important opportunistic pathogen in solid organ and hematopoietic cell transplantation, particularly in lung transplant recipients (LTRs). LTRs mismatched for CMV (donor+/recipient−; D+ R−) are at high risk for active CMV infection and increased mortality; however, the immune correlates of viral control remain incompletely understood. We prospectively studied 27 D+ R− LTRs during primary CMV infection to determine whether acute CD4+ T cell parameters differentiated the capacity for viral control during early chronic infection. Unexpectedly, the T-box transcription factor, T-bet, was expressed at low levels in CD4+ compared with CD8+ T cells during acute primary infection. However, the capacity for in vitro CMV phosphoprotein 65–specific proliferation and CD4+ T-bet+ induction differentiated LTR controllers from early viremic relapsers, correlating with granzyme B loading and effector multifunction. Furthermore, impaired CMV-specific proliferative responses from relapsers, along with T-bet, and effector function could be significantly rescued, most effectively with phosphoprotein 65 Ag and combined exogenous IL-2 and IL-12. Acute CD4+ T cell CMV–specific proliferative and effector responses were highly IL-12–dependent in blocking studies. In addition, we generated monocyte-derived dendritic cells using PBMC obtained during primary infection from relapsers and observed impaired monocyte-derived dendritic cell differentiation, a reduced capacity for IL-12 production, but increased IL-10 production compared with controls, suggesting an APC defect during acute CMV viremia. Taken together, these data show an important role for CMV-specific CD4+ effector responses in differentiating the capacity of high-risk LTRs to establish durable immune control during early chronic infection and provide evidence for IL-12 as a key factor driving these responses.