The phenomenon of heparin resistance (HR) is characterized by high doses of unfractionated heparin (UFH) being required to bring activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) within therapeutically desired ranges, or by the impossibility of reaching these ranges. At UFH dosages > 35,000 IU/d, HR should be considered a factor. The most frequent cause of HR is deficiency of antithrombin (AT), the presence of which is essential for UFH to exert its anticoagulatory effect. AT in concentrate form may be applied to overcome AT-dependent HR. The main clinically relevant situations in which AT-dependent HR occurs, with possible indication of AT substitution, are congenital AT deficiency, asparaginase therapy, disseminated intravascular coagulation (DIC) and administration of high doses of heparin during extracorporeal circulation, where it is significant, due to the need to maintain a very high ACT (> 400 s), that use of heart-lung machines is associated with an HR incidence of approximately 20%. The following procedure is recommended when there is no DIC and when extracorporeal circulation is not used: if HR is suspected and AT activity is < or = 60%, UFH should first be reduced to 500 IU/h (to prevent bleeding complications), before AT is substituted. AT activity should then exceed 80%. Under normalized and stable AT activity, the UFH dose should be adjusted such that aPTT is within a range of 60-100 s. If anticoagulation over a longer term is indicated, then overlapping anticoagulation with a vitamin K antagonist should be started as quickly as possible.