Background: Approximately 50% of percutaneous coronary interventions in the United States are performed with unfractionated heparin and no IIb/IIIa agent. The operator must weigh the risks and benefits of more intensive anticoagulation during these percutaneous interventions. This study helps clarify the relationship between patient and procedural factors, such as the intensity of heparin anticoagulation as measured by activated clotting time (ACT), and the risk of blood loss and bleeding complications. Methods: Four hundred twenty-nine patients undergoing elective or urgent percutaneous coronary intervention were followed up prospectively for 72 hours after intervention for clinical bleeding complications. Blood loss, defined as the difference between preprocedural and nadir postprocedural hematocrit adjusted for interval transfusions, was also tracked. In-laboratory ACTs, as well as other potential clinical and procedural predictors of blood loss and bleeding risk, were collected and analyzed. Results: Maximum in-laboratory ACT was significantly related to blood loss as measured by the change in hematocrit (P =. 017) and to the risk of major bleeding complications (P =. 002). In multivariate analysis, patient age (P =. 004), sex (P =. 014), procedure length (P <. 001), and additional interventions (P <. 001) were significant, independent predictors of blood loss. Major bleeding complications were significantly, independently predicted by patient age (P <. 001), additional interventions (P =. 015), and maximum in-laboratory ACT (P <. 001). Conclusions: Compared with the other clinical and procedural predictors of bleeding complications, maximum in-laboratory ACT was second only to patient age in significance as a multivariate predictor of postprocedural bleeding complications. Maximum in-laboratory ACT was found to be the most significant modifiable univariate and multivariate predictor of clinical bleeding complications after percutaneous coronary intervention. Particularly in patients with nonmodifiable risk factors for blood loss and bleeding complications such as advanced age, female sex, and multiple and prolonged procedures, avoiding high intensity anticoagulation with unfractionated heparin is associated with lower bleeding risk.