Drug interactions are a common occurrence with calcineurin inhibitors. We describe the case of a heart transplant recipient who developed increased tacrolimus blood levels after the administration of intravenous azithromycin and ceftriaxone. Tacrolimus levels decreased after the discontinuation of ceftriaxone and switch from intravenous to oral azithromycin. Transplant recipients who receive intravenous azithromycin and/or ceftriaxone concomitantly with tacrolimus therapy should be monitored closely for the duration of the antibiotic administration.