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Abstract Background Surgical site infections after craniotomy (SSI-CRAN) significantly impact patient outcomes and healthcare costs by increasing length of stay and readmission and reoperation rates. However, to our knowledge, no study has yet analysed the economic impact of a surgical care bundle for preventing SSI-CRAN. The aim is to analyse the hospital cost saving after implementation of a care bundle for the prevention of SSI-CRAN. Methods A retrospective cost-analysis was performed, considering two periods: pre-care bundle (2013–2015) and care bundle (2016–2017). A bottom-up approach was used to calculate the costs associated with infection in patients who developed a SSI-CRAN in comparison to those who did not, in both periods and on a patient-by-patient basis. The derived cost of SSI-CRAN was calculated considering: (1) cost of the antibiotic treatment, (2) cost of length of stay in the neurosurgery ward within the 1-year follow up period, (3) cost of the re-intervention, and (4) cost of the implant for cranial reconstruction, when necessary. Results A total of 595 patients were included in the pre-care bundle period and 422 in the care bundle period. Mean cost of a craniotomy procedure was approximately €8000, rising to €24,000 in the case of SSI-CRAN. Mean yearly hospital costs fell by €502,857 in the care bundle period (€714,886 vs. €212,029). Extra costs between periods were mainly due to increased length of hospital stay (€573,555.3 vs. €183,958.9; difference: €389,596.4), followed by the cost of implant for cranial reconstruction (€69,803.4 vs. €9,936; difference: €59,867.4). Overall, implementation of the care bundle saved the hospital €500,844.3/year. Conclusion The implementation of a care bundle for SSI-CRAN had a significant economic impact. Hospitals should consider the deployment of this multimodal preventive strategy to reduce their SSI-CRAN rates, and also their costs.