Background: Medication regimen complexity describes multiple characteristics of a patient’s prescribed drug regimen. Heart transplant recipients must comply with a lifelong regimen that consists of numerous medications. However, a systematic assessment of medication regimen complexity over time has not been conducted in this, or any other, transplant population. Objective: The objective of this study was to quantify patient-level medication regimen complexity over time following primary heart transplantation and heart retransplantation, using the validated patient-level Medication Regimen Complexity Index (pMRCI) tool. Methods: Medication lists were reviewed at transplant discharge and years 1, 3, and 5 post–primary heart transplant, and at transplant discharge and years 1 and 3 post–heart retransplantation. Medications were categorized as transplant-specific, other prescription, and over-the-counter (OTC). Results: In primary heart transplant recipients (n = 60), mean total medication count was 14.3 ± 3.4 at transplant discharge and did not change significantly over time ( P = 0.64). Transplant-specific medication count decreased significantly from discharge (2.9 ± 0.4) to year 5 (2.3 ± 0.6); P = 0.02. However, 32% of patients were taking 16 or more total medications at year 5 posttransplant. More than 70% of the pMRCI score was attributed to other prescription and OTC medications, which was largely driven by dosing frequency in this cohort. Medication complexity did not differ significantly between heart retransplant recipients (n = 11) and matched primary heart transplant controls (n = 22). Conclusion: Together, these data highlight the substantial medication burden after heart transplantation and reveal opportunities to address medication regimen complexity in this, and other, transplant populations.