Hypersensitivity to unfractionated and low-molecular-weight heparins and semisynthetic heparinoids is increasingly common. 7 female patients between 30 and 74 years with delayed-type allergy to heparins and semisynthetic heparinoids were investigated for (cross)-reactivity to fondaparinux, a new pentasaccharide with selective factor Xa inhibition. All patients showed delayed-type reactions to heparins and some additional cross-reaction to a heparinoid on intracutaneous testing. 6/7 tolerated fondaparinux on intradermal testing as well as on subcutaneous challenge testing. However, the 7th patient developed a characteristic delayed-type reaction to both skin tests with fondaparinux. Fondaparinux is a new synthetic pentasaccharide with a molecular weight of 1.728 Da. In some patients with cross-reactivity between various heparins and semisynthetic heparinoids, lepirudin, a recombinant hirudin, may be a safe and effective alternative. However, combined allergy to hirudin and heparins has been reported. Sometimes, intravenous administration of heparins or heparinoids may be tolerated. However, these patients are at risk of developing a systemic reaction. The pathogenesis of heparin hypersensitivity is not fully understood. Heparins may act as haptens by binding to dermal and/or subcutaneous structural proteins. The chemical structures of heparins and fondaparinux are different concerning their alpha- and beta-configuration and the molecular weight. However, some of their functional groups are nearly identical and therefore similar chemical and pharmacological reactivity is to be expected. Fondaparinux seems to be a valuable alternative in most cases of heparin and hirudin hypersensitivity. The clearly rare cross-reaction between fondaparinux and heparins, now confirmed by us, may be due to differences in the response to haptens.