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OBJECTIVE The objective of this study was to quantify surgical site infection (SSI) rates after cranial neurosurgery in a tertiary care hospital, identify risk factors for SSI, and evaluate the impact of standardized surveillance and an infection prevention bundle (IPB). METHODS The authors compared SSI rates during 7 months before and after the intervention. The IPB included standardized patient preparation, perioperative antibiotic/antiseptic use, barrier precautions, coaching of surgeons, and the implementation of a specialized technical operation assistant team. RESULTS Three hundred twenty-two unselected consecutive patients were evaluated before the IPB, and 296 were evaluated after implementation. Infection rates after 1 year decreased from 7.8% (25/322) to 3.7% (11/296, p = 0.03) with similar mortality rates (14.7% vs 13.8%, p = 0.8). The isolated bacteria included Staphylococcus aureus (42%), Cutibacterium acnes (22%), and coagulase-negative staphylococci (14%). Organ/space infections dominated with 67%, and mostly consisted of subdural empyema and meningitis/ventriculitis. Among the 36 SSIs, 13 (36%) occurred during hospitalization, and 29 (81%) within the first 3 months of follow-up. In multivariable analysis including established risk factors described in the literature, non-CNS neoplasia (odds ratio [OR] 3.82, 95% confidence interval [CI] 1.39-10.53), postoperative bleeding (OR 4.09, 1.44-11.62), operations performed by or under supervision of a senior faculty surgeon (OR 0.38, 0.17-0.84), and operations performed after the implementation of standardized surveillance and an IPB (OR 0.38, 0.17-0.85) significantly influenced the infection rate. CONCLUSIONS The introduction of an IPB combined with routine surveillance and personal feedback was associated with a 53% reduced infection rate. The lower infection rates of senior faculty and the strong association between postoperative bleeding and infection underline the importance of both surgical experience as well as thorough supervision and coaching of younger surgeons.