Coronary lesions in patients with advanced cardiac allograft vasculopathy (CAV) are frequently treated with percutaneous coronary intervention. Despite high primary success rates, long-term outcome is significantly impaired by a high incidence of restenosis. In nontransplanted patients, the use of drug-eluting stents (DES) significantly decreases the rate of coronary in-stent restenosis. We report a case treated for cardiac allograft coronary in-stent restenosis with a sirolimus-eluting stent presenting with recurrent in-stent restenosis at follow up. However, the pattern of in-stent restenosis changed from diffuse proliferative disease in the bare-metal stent to a focal pattern in the sirolimus-eluting stent concordant with observations in nontransplanted patients. This case highlights the need for further studies addressing the effect of DES for the prevention of restenosis both in de novo as well as in-stent restenotic lesions in patients with CAV.