Background The aim of this analysis was to define the risk factors associated with the problematic dose titration of unfractionated heparin (UFH) in high-risk non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients. Methods and Results The study group comprised 267 patients with high-risk NSTE ACS managed with an early invasive strategy and treated with the recommended dose of UFH. The subsequent dose was adjusted after measurement of activated partial thromboplastin time (aPTT), using the nomogram. The goal for aPTT was 1.5-2.5-fold of the control value. At 6 h after starting therapy 29% of patients had a therapeutic initial aPTT value; half of them were over-anticoagulated, and 22% were undertreated. By continuing therapy, the proportion of optimally treated patients increased; after 12 h of treatment 40% of patients reached the therapeutic dose, and 58% after 24 h. Undertreatment was a problem in ≤65-year-old men. Women and older patients have a higher risk of overdose. The patients with a therapeutic dose of UFH had the lowest occurrence of major ischemic adverse events. Conclusions Expert consensus on more precise dose guidelines for UFH is needed. The dose needs to be not only weight, but also age and sex, adjusted. (Circ J 2008; 72: 1674 - 1679)