Gliadel wafers (1,3-bis [2-chloroethyl]-1-nitrosourea; Guilford Pharmaceuticals) are approved for the treatment of malignant gliomas; however, the incidence of and risk factors associated with infection with respect to this new technology are unknown. We identified 32 patients who received Gliadel wafers from December 1996 through October 1999. Nine patients (28%) developed >or=1 surgical site infection (SSI), which included 4 cases of brain abscess. All 3 patients who received vancomycin for surgical prophylaxis developed an SSI. In addition, multivariable analysis revealed an association between infection and a clinical diagnosis of depression. The National Nosocomial Infection Surveillance Surgical Site Index did not predict the onset of SSI after Gliadel wafer implantation. Patients who received a Gliadel wafer had a higher incidence of infection than previously has been reported, and additional studies are required to better quantify this risk and describe the epidemiology of such infections.