PURPOSE: Cardiac surgery with cardiopulmonary bypass requires systemic anticoagulation, defined by an activated clotting time (ACT) of 400-480 sec. Patients with altered heparin responsiveness require disproportionately higher doses of heparin to achieve this target ACT. A common risk factor for heparin resistance is preoperative heparin therapy. Recently, therapy with low molecular weight heparin (LMWH) has become an acceptable substitute for prolonged heparin therapy. The current study examines the effect of preoperative LMWH therapy on subsequent heparin responsiveness during cardiac surgery. METHODS: Records of patients undergoing cardiac surgery with cardiopulmonary bypass over a period of four months were reviewed. We identified patients who, during the week preceding surgery, had received prolonged (>24 hr) therapy with either sc LMWH (LMWH group) or continuous iv unfractionated heparin (Heparin group). A Control group consisted of patients who received neither heparin nor LMWH preoperatively. The heparin sensitivity index (calculated as the first change in ACT from baseline divided by the first intraoperative heparin dose, normalized to body weight), was compared among groups using ANOVA. RESULTS: One hundred and thirty-nine patients were included in the analysis. The heparin sensitivity index was 33-45% higher in the Control group (1.6+/-0.7 sec.IU-1.kg-1; P<0.0001) compared to the LMWH (1.2+/-0.4 sec.IU-1.kg-1) and Heparin (1.1+/-0.5 sec.IU-1.kg-1) groups. In a multivariable model, the use of preoperative LMWH remained a significant predictor of reduced intraoperative heparin responsiveness (P=0.002). CONCLUSION: Prolonged preoperative LMWH therapy, similar to the known effect of prolonged unfractionated heparin infusion, reduces subsequent intraoperative response to heparin.