BACKGROUND: Delayed-type hypersensitivity (DTH) reactions in patients receiving heparin may occur with both unfractionated (UFHs) and low molecular weight heparins (LMWHs). Skin testing is a clue to detect tolerated heparin or heparinoid preparations for further treatment. OBJECTIVE: To study in vivo cross-reactivity between LMWHs, UFHs, and danaparoid by skin testing in patients with suspected DTH to heparin. METHODS: Patients who fulfilled the criteria for the diagnosis of suspected heparin allergy were involved in a prospective study after informed consent. Patients presented with or had a history of typical erythematous plaques at the heparin injection sites. Skin testing was performed by subcutaneous injections of heparin (300-500 IU anti-Xa activity) and danaparoid (375 IU, eight patients). Desirudin (27,000 IU) was tested in three patients. We read skin reactions after 24, 48, and 96 hours and after 7 days. RESULTS: Fourteen female and 4 male patients were included in our series. Erythematous plaques had been reported or developed after 14-35 days in patients during first-time heparin treatment and after 2-10 days in reexposed patients. Positive skin test results were seen in 15 of 18 (83.3%) patients. Of these, 11 (73.3%) showed cross-reactivity between heparins and/or danaparoid. Six patients reacted to LMWHs only, nine patients to both LMWHs and UFHs. Danaparoid was tolerated in six of eight patients; desirudin was tolerated in all three patients tested. CONCLUSIONS: DTH to heparins is characterized by considerable cross-reactivity between LMWHs, UFHs, and danaparoid. UFHs may be tolerated even if LMWHs are not. Subcutaneous testing of a panel of heparins, danaparoid, and desirudin (hirudin) is recommended to determine acceptable treatment options for patients allergic to specific heparins.