The risk of hemorrhagic complications with anticoagulation therapy in patients following intracranial surgery has prevented investigation of the potential use of heparin in the early postoperative period. The authors have evaluated the safety of anticoagulation therapy following experimental craniotomy in male Holtzman rats. The dose and schedule of heparin administration, which elevated and maintained the activated partial thromboplastin time (APTT) within the therapeutic range of 1 1/2 to 3 X control APTT, was alternating doses of 400 and 500 IU/kg injected subcutaneously every 6 hours. This schedule was initiated 2, 4, 7, 10, and 14 days after craniotomy and was continued for 72 hours thereafter. The results demonstrated that the incidence of intracerebral hemorrhage declined as the postoperative interval prior to initiation of anticoagulation increased. If anticoagulation therapy was initiated during the first 7 postoperative days, the risk of intracerebral hemorrhage was high (mean 14.7%): however, if an additional 3 to 7 days elapsed prior to initiation of anticoagulation, the incidence of intracerebral hemorrhage dropped significantly (mean 0%) (p less than 0.05). These results suggest that anticoagulation therapy can be safely initiated 10 to 14 days after craniotomy.