Background: Cutaneous malignancy is a major cause of morbidity in organ transplant recipients. Objective: Our purpose was to report on skin cancer in Australian heart transplant recipients with analysis of HLA factors. Methods: We reviewed histologically proven skin cancers in the first 455 patients undergoing organ transplantation in Sydney, Australia. Results: The cumulative incidence of skin cancer was 31% at 5 years and 43% at 10 years with a squamous cell carcinoma/basal cell carcinoma ratio of 3:1. Caucasian origin, increasing age at transplantation, and duration of follow-up were significantly associated with skin cancer. Skin cancer accounted for 27% of 41 deaths occurring after the fourth year. Recipient HLA-DR homozygosity was associated with skin cancer overall, whereas HLA-DR7 was a protective factor in skin cancer overall, squamous cell carcinoma, and Bowen’s disease. HLA-A1 and HLA-A11 were significant protective factors in Bowen’s disease. Conclusion: Skin cancer is a major cause of morbidity and long-term mortality in heart transplant patients. (J Am Acad Dermatol 1999;40:27-34.)