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Background: Sirolimus has provided the option for calcineurin inhibitor (CNI)-free immunosuppressive therapy in both solid organ transplant (SOT) and hematopoietic stem cell transplantation (HSCT). However, long-term use of sirolimus has been reported to be associated with a high incidence of cutaneous side effects in SOT, particularly acneiform lesions. Materials and Methods: We studied the incidence of acneiform lesions and the risk factors in 41 HSCT recipients between ages 4 and 64 years, undergoing HSCT for malignant (n = 29) and non-malignant diseases (n = 12) from haploidentical family donors. Results: Seven patients developed acneiform lesions at the median of 85 days (range, 45-105 days). Acneiform lesions occurred in 6/11 patients on sirolimus and in only 1/30 patients not receiving sirolimus (P = 0.001). This was more frequent in patients with non-malignant disorders (5/12 versus 2/29, P = 0.01) and those receiving graft from female donors (7/23 versus 0/18, P = 0.01). Conclusions: Despite being frequently reported in SOT, this is the first such report in HSCT. Our study suggests that prolonged use of sirolimus might be associated with high incidence of acneiform lesions in haploidentical HSCT recipients with non-malignant diseases, particularly in those receiving graft from a female donor. We discuss the possible reasons for these findings and the putative mechanism of acneiform lesions in these patients