OBJECTIVE Vasospasm as a complication of subarachnoid hemorrhage is a major concern in clinical practice. The systemic drugs in current use are of limited value. Topical, intrathecal, or intraarterial papaverine administered during surgical or angiographic procedures is a potent vasodilating drug; however, hypotension limits its systemic application. Local application of papaverine in a biodegradable controlled- or sustained-release matrix is proposed for vasospasm prophylaxis to be used in patients scheduled for aneurysm surgery. METHODS Controlled-release papaverine (PapaCR) drug pellets were prepared using the biodegradable aliphatic polyester poly(DL-lactide-co-glycolide) as the carrier matrix. In vitro tests were performed to determine drug kinetics. One hundred seventeen patients, 73 assigned to the control group and 44 assigned to the PapaCR-treated group, participated in this study. Patients who were deemed to be at high risk for the development of vasospasm were selected to participate in the study. During aneurysm surgery, drug pellets were placed in cisterns over arterial segments. In two patients, cerebrospinal fluid was sampled every 6 hours for the first 5 days through a lumbar catheter that had been inserted at the beginning of aneurysm surgery. The incidence of clinical vasospasm and Glasgow Outcome Scale scores in the patients were evaluated statistically. The results of in vitro studies showed that effective local concentrations of papaverine could be maintained for more than 10 days. The first-degree drug-release profile was demonstrated using this design. In clinical studies no adverse effects due to the drug were seen. The PapaCR effectively prevented development of clinical vasospasm. and outcome scores were significantly better in patients in the treated group. CONCLUSIONS Local application of controlled- or sustained-release papaverine can be safely used in preventing vasospasm.