There are limited data available on the bioequivalence of generic and brand-name tacrolimus in pediatric and heart transplant patients. We characterized changes in 12-hour trough concentrations and clinical outcomes after transition from brand to generic tacrolimus in pediatric thoracic organ transplant recipients. Patients with a pharmacy-confirmed date of switch between generic and brand tacrolimus were identified, as well as a matched control group that did not switch for comparison. We identified 18 patients with a confirmed date of switch, and in 12 patients that remained on the same dose, trough concentrations were 14% less than when they were on brand (p = 0.037). The average change was −1.15 ± 1.76 ng/mL (p = 0.045). The control group did not experience a change in trough concentration and was different than the switched group (p = 0.005). There were no differences in dosage changes or kidney or liver function. In the year after switch, 24% of patients who were switched to generic experienced a rejection event vs. 18% in the patients on brand. We suggest a strategy of monitoring around the time of transition, and education of the patient/family to notify the care team when changes from brand to generic or between generics occur.