Sirolimus (SRL) has been used for most islet recipients over the past 5 years. It provides balanced immunosuppression in combination with low-dose calcineurin inhibitors, while avoiding corticosteroids. This regimen decreases the risk of nephrotoxicity, neurotoxicity and diabetogenicity. SRL has also been used selectively in clinical liver and kidney transplantation. A number of common side effects including anemia, leucopenia, thrombocytopenia, hypercholesterolemia, mouth ulceration, joint pain, extremity edema and impaired wound healing have been associated with the use of SRL. As SRL is used more frequently, evidence has been gathered on its rare but severe side effects. We report 2 patients who underwent islet transplantation and developed symptomatic small bowel ulceration that resolved after complete withdrawal of SRL. Although small bowel ulceration is rare, it can potentially progress to more serious complications if not treated adequately. Our experience highlights an uncommon but potentially serious adverse effect of high-dose SRL in islet recipients.