Sirolimus is an immunosuppressant drug used to prevent organ rejection in transplant patients. We describe a man with sirolimus-associated pruritus and review the features of this adverse event in other individuals receiving this drug. The patient was a 67-year-old heart transplant recipient receiving sirolimus as part of his immunosuppressive regimen. He developed severe pruritus over the distal extremities, face, and earlobes six months after starting the drug. The symptoms became progressively worse as he continued to receive this medication. Temporary elimination of the drug resulted in cessation of his itching. Subsequently, sirolimus was discontinued and everolimus was started; this provided temporary relief of his pruritus. PubMed was used to review the following terms: “sirolimus”, “itch”, and “pruritus.” Relevant papers and their references were reviewed. We are aware of only one other patient in whom pruritus necessitated cessation of treatment with sirolimus. Systemic pruritus is a rare adverse event associated with sirolimus. It can occur in both heart and liver transplant patients, beginning several months after transplant, and typically persists. Dose reduction may improve symptoms. Discontinuation of the medication or use of alternative immunosuppressants may be necessary for complete symptom relief.