The role of secondary cytomegalovirus (CMV) prophylaxis, defined as the continuation of valganciclovir to prevent relapse after the successful treatment of CMV disease, is not well understood.Methods. Cases of CMV disease in patients who underwent kidney or liver transplantation from January 2001 to January 2010 were reviewed to determine if the use of secondary prophylaxis was associated with fewer relapses or other favorable outcomes. Secondary prophylaxis was used at the discretion of each treating clinician, without an institutional protocol. Results. Twenty-two cases of CMV disease in kidney transplant recipients and 20 cases in liver transplant recipients were included. Relapsed CMV disease was significantlymore common among kidney transplant recipients (5/22 vs. 0/20, P = 0.049). Of 22 kidney transplant recipients, 16 received secondary prophylaxis. After a mean of 3.7 years, relapsed CMV disease occurred in three of 16 patients who received secondary prophylaxis and in two of six who did not. Among liver transplant recipients, only two of 20 patients received secondary prophylaxis. After a mean of 3.2 years, no relapsed CMV disease occurred. The use of secondary prophylaxis was not significantly associated with fewer episodes of CMV relapse, graft loss, or death. Time to clearance of CMV viremia during treatment was significantly longer in those who relapsed (mean, 30 days vs. 20 days; P = 0.037). Conclusion. These findings suggest that secondary CMV prophylaxis may not provide additional benefit after the successful treatment of CMV disease, particularly among liver transplant recipients.