Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in solid organ transplant recipients (SOTRs). Secondary prophylaxis (SP) is not routinely recommended by guidelines on the management of CMV in SOTR but may be considered in certain higher-risk situations. A comprehensive search of English language publications up to September 2023 was performed. The primary outcome was CMV relapse, defined as the recurrence of DNAemia or disease. Secondary outcomes included graft loss, mortality, and hematological toxicity. Meta-analysis used the random-effects model. The study protocol is registered in PROSPERO (no. CRD42022357028). Six retrospective comparative studies were included. A total of 520/727 (72%) of SOTR received SP with valganciclovir. The meta-analysis did not demonstrate a significant difference in CMV relapse (odds ratio [OR] 1.15, 95% confidence interval [CI] 0.79-2.63). Heterogeneity between the studies was low (I2 = 0%, p = 0.57). SP was significantly associated with a reduction in mortality (OR 0.2, 95% CI 0.07-0.54) but not graft loss (OR 0.67, 0.17-2.63). There was no significant difference in CMV relapse among kidney-specific SOTR (OR 1.38, 95% CI 0.65-2.96). Evidence from six nonrandomized studies is limited and cannot support a recommendation for or against routine SP in SOTR treated for CMV infection. Awaiting prospective-controlled trials, the decision about SP should depend on individualized risk-profile assessments by experienced clinicians.