Background. It is unknown how death with a functioning graft (DWFG) is affected in renal transplant recipients who receive prophylaxis for cytomegalovirus (CMV) infection. Methods. Data from 61,927 adult recipients of a deceased donor kidney transplant in 1990 to 2012 registered with the Collaborative Transplant Study were analyzed. Results. Cytomegalovirus prophylaxis was administered in 18%, 75%, 27% and 34% of R-/D-(recipient-negative, donor-negative), R-/D+, R+/D- and R+/D+ transplants, respectively. Only in R-/D+ transplants was CMV prophylaxis associated with significantly improved patient survival versus no prophylaxis (P<0.001). Unexpectedly, in the R-/D+ subgroup, DWFG because of infection was not significantly affected by use of CMV prophylaxis (P=0.16) but death from cardiovascular disease was significantly lower (P<0.001). Cox regression analysis confirmed that the primary impact of CMV prophylaxis on DWFG in R-/D+ transplants was because of reduced cardiovascular death (hazard ratio, 0.66; 95% confidence interval, 0.51-0.85; P=0.002), an effect restricted to patients aged 40 years or older (hazard ratio, 0.61; 95% confidence interval, 0.46-0.81; P<0.001). Conclusion. We conclude that CMV prophylaxis is associated with a significant benefit for risk of cardiovascular DWFG among R-/D+ kidney transplant patients aged >= 40 years. Cytomegalovirus prophylaxis appears particularly critical in this patient subpopulation.