Heparin-induced thrombocytopenia (HIT) is an antibody-mediated prothrombotic disorder triggered by PF4-binding polyanions, usually heparin. The pentasaccharide anticoagulant, fondaparinux, despite its negative charge and structural similarity to heparin, does not usually promote antibody binding to PF4 (owing to absent/weak 'cross-reactivity'). Thus, despite its ability to trigger anti-PF4/heparin antibodies ('immunogenicity'), fondaparinux has low - but not zero - risk of inducing HIT de novo, or of exacerbating HIT when antibodies are already present. Indeed, despite rare reports of fondaparinux-induced HIT, this 'dissociation' between immunogenicity and cross-reactivity suggests that fondaparinux should be effective in treating HIT, as supported by several observational studies. An emerging issue: will clinicians accept this favorable experience of fondaparinux for treating HIT when a lack of randomized trials will hinder regulatory approval for this indication?