Reactivation of cytomegalovirus (CMV) from latency is a frequent complication of organ transplantation, and the molecular mechanism by which this occurs is unknown. Previous studies have shown that allogeneic stimulation induces reactivation of human CMV (HCMV) in vitro (64). We find that transplantation of vascularized allogeneic kidneys induces murine CMV (MCMV) and HCMV immediate-early (ie) gene expression. This induction is accompanied by increased expression of transcripts encoding inflammatory cytokines, including tumor necrosis factor (TNF), interleukin-2, and gamma interferon, and by activation of NF-κB. TNF alone can substitute for allogeneic transplantation in inducing HCMV and MCMV iegene expression in some tissues. Our studies suggest that reactivation is a multistep process which is initiated by factors that induceie gene expression, including TNF and NF-κB. Allogeneic transplantation combined with immunosuppression may be required to achieve complete reactivation in vivo.