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Background Few data support use of 6 over 3 months of antiviral prophylaxis for cytomegalovirus (CMV) disease prevention in donor seropositive/recipient seronegative (D+R−) heart transplant recipients (HTR). Methods We retrospectively assessed CMV disease and outcomes in 310 adult HTR between July 5, 2005, and December 30, 2016, at our center. Valganciclovir (VGCV) prophylaxis was given for 3-6 months in the D+R− group. Multivariable models evaluated risk factors for CMV disease in patients who received 3 vs 6 months (±1 month) of prophylaxis, with investigation of inverse probability weighting to correct for confounding variables. Results The incidence of CMV disease among all patients and the D+R− group was 8.7% (27/310) and 26.5% (22/83), respectively, and included syndrome in 22.2% (6/27) and end-organ involvement in 77.8% (21/27). In a multivariable model, 6 vs 3 months of antiviral prophylaxis was not associated with reduced risk for CMV disease (OR 2.28 [95% CI 0.66, 7.91], P = .19). CMV disease in D+R− HTR was associated with higher rates of hospitalization (87.5% [14/16] vs 6.3% [1/16], P < .001) and for a longer duration than in matched D+R− controls without disease. Conclusions Cytomegalovirus disease remains a major cause of morbidity in D+R− HTR. In contrast to documented benefit in D+R− lung and kidney recipients, VGCV duration of 6 months was not associated with a lower incidence of CMV disease in D+R− HTR compared to 3-month duration and should be reconsidered in this patient population.

_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/tid.13255