Background: There is debate whether cytomegalovirus immunoglobulin (CMV‐Ig) is also needed for CMV prevention in heart transplant recipients in the era of good anti‐viral drugs. Methods: We conducted a cost‐savings quality initiative on CMV‐Ig eventually leading to discontinuation of routine use of CMV‐Ig for CMV prevention. Subsequently, a retrospective cohort study was conducted, comparing patients in cohort I (CMV‐Ig plus anti‐viral drugs, 2013‐2015) to cohort II (anti‐virals alone, 2015‐2017). The medication acquisition costs and outcomes of CMV infection were assessed. Results: There were 39 total patients: 22/39(56%) in cohort I, with mean follow‐up of 35.14 ± 17.38 months and 17/39(44%) in cohort II, mean follow‐up of 19.12 ± 7.08 months. In cohort I, 5/22(22.7%) patients died from causes unrelated to CMV and 0/17 in cohort II died. There were 5/22(22.7%) patients in cohort I, and 2/17(9%) patients in cohort II that developed CMV infection (P =.508). Freedom from rejection was 81.8% (18/22) in cohort I, and 71% (12/17) in cohort II (P =.46), and 100% for allograft vasculopathy. There was significant reduction in medication acquisition cost following the protocol change of $260 839 or $15 343 per patient. Conclusion: Our study demonstrated an acquisition cost savings with similar clinical outcomes utilizing anti‐viral CMV prophylaxis alone vs anti‐viral prophylaxis plus CMV‐Ig. [ABSTRACT FROM AUTHOR]