Bleeding is a major concern during percutaneous nephrolithotomy (PCNL), especially with the use of multiple tracts. This prospective study aimed to identify factors affecting blood loss during PCNL. Data were collected prospectively from 236 patients undergoing 301 PCNL procedures at our institute since June 2002. Blood loss was estimated by the postoperative drop in hemoglobin factored by the quantity of any blood transfusion. Various patient-related and intraoperative factors were assessed for association with total blood loss or blood transfusion requirement using stepwise multivariate regression analysis. The average hemoglobin drop was 1.68 +/- 1.23 g/dL. Stepwise multivariate regression analysis showed that the occurrence of operative complications (P or =2) tracts (P = 0.003), size of the tract (P = 0.001), renal parenchymal thickness (P = 0.05), and diabetes (P = 0.05) were significant predictors of blood loss. The overall blood transfusion rate for all patients was 7.9%. Preoperative hemoglobin, multiple tracts, stone size, and total blood loss were significant in predicting perioperative blood transfusion requirement. Factors such as age, hypertension, renal insufficiency, urinary infection, the degree of hydronephrosis, stone bulk, and the function of the ipsilateral renal unit did not have any effect on the blood loss. Technical factors such as the operating surgeon and the calix of entry also did not affect the blood loss. Diabetes, multiple-tract procedures, prolonged operative time, and the occurrence of intraoperative complications are associated with significantly increased blood loss. Atrophic parenchyma and past ipsilateral intervention are associated with reduced blood loss. On the basis of this evidence, maneuvers that may reduce blood loss and transfusion rate include ultrasound-guided access, use of Amplatz or balloon dilatation systems, reducing the operative time, and staging the procedure in cases of a large stone burden or intraoperative complications. Reducing the tract size in pediatric cases, nonhydronephrotic systems and those with a narrow infundibulum, and secondary tracts in a multiple-tract procedure may also reduce blood loss during PCNL.