Nuclear factor of activated T-cells (NFAT) is a transcription factor family, in the clinic – including during allogeneic hematopoietic stem cell transplantation (allo-HCT) - addressed by calcineurin inhibition (CNI). This blocks its activation, thereby graft-versus-host disease (GvHD) but enhances the risk of cytomegalovirus (CMV) reactivation. In immunocompetent individuals, CD8⁺ T cells efficiently fight and further control latent CMV infections. However, this control is lost in patients after conditioning for allo-HCT. Since we previously showed that bone marrow transplants containing NFAT-deficient T cells ameliorates GvHD like CNI, we evaluated the impact of MCMV infections on the course of GvHD and whether T cell-specific NFAT inhibition is still protective. Indeed, while the acute MCMV infection of allo-transplanted mice aggravated the clinical score, the presence of NFAT-deficient T cells still ameliorated GvHD in comparison to wildtype (WT) T cells. Now, we tested donor T cells, CMV-naïve (D-) vs CMV-experienced (D+) in latently MCMV-infected recipients (R+). Consistent with our former data, in the D+/R+ serostatus constellation the severity of clinical scores and weight loss was limited using NFAT-deficient T cells six days post allo-HCT. However, over time the protective effect of single NFAT-deficient T cells was reversed. Of note, in vitro polyclonally pre-stimulated NFAT single-deficient T cells exerted a similar aggravating phenotype, while only Nfatc1^-/-c2^-/- T cells ameliorated GvHD stably. In contrast, upon transplantation of naive T cells into latently infected recipients (D-/R+), clinical scores and weight loss could be kept to a minimum in the presence of single NFAT-ablated T cells. We conclude that MCMV infection does not perturb the protective NFAT inhibition for GvHD development and that loss of one NFAT family member still allows an anti-CMV response. Further, we hope to define a specific activation/memory state of NFAT-deficient CMV-specific T cells that ensures long-term protection against GvHD and CMV reactivation.