BACKGROUND: Little is known about the incidence and causes of heparin-induced skin lesions. The 2 most commonly reported causes of heparin-induced skin lesions are immune-mediated heparin-induced thrombocytopenia and delayed-type hypersensitivity reactions. METHODS: We prospectively examined consecutive patients who received subcutaneous heparin (most often enoxaparin or nadroparin) for the presence of heparin-induced skin lesions. If such lesions were identified, we performed a skin biopsy, platelet count measurements, and antiplatelet-factor 4 antibody and allergy testing. RESULTS: We enrolled 320 patients. In total, 24 patients (7.5%, 95% confidence interval [CI] 4.7%-10.6%) had heparin-induced skin lesions. Delayed-type hypersensitivity reactions were identified as the cause in all 24 patients. One patient with histopathologic evidence of delayed-type hypersensitivity tested positive for antiplatelet-factor 4 antibodies. We identified the following risk factors for heparin-induced skin lesions: a body mass index greater than 25 (odds ratio [OR] 4.6, 95% CI 1.7-15.3), duration of heparin therapy longer than 9 days (OR 5.9, 95% CI 1.9-26.3) and female sex (OR 3.0, 95% CI 1.1-8.8). INTERPRETATION: Heparin-induced skin lesions are relatively common, have identifiable risk factors and are commonly caused by a delayed-type hypersensitivity reaction (type IV allergic response).