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Increased Risk of Surgical Site Infections With Clindamycin Prophylaxis in Clean Craniotomy. BACKGROUND AND OBJECTIVES: Postoperative central nervous system infections remain a major complication following craniotomy, with reported incidence ranging from 2.2% to 9.6%. The administration of preoperative antibiotic prophylaxis, particularly cephalosporins, has significantly reduced these infections. However, in patients reporting a penicillin allergy, alternatives such as vancomycin or clindamycin are recommended despite ongoing concerns about their efficacy. Recent studies have associated clindamycin use with a higher risk of surgical site infections (SSI) in various surgical specialties. This study aimed to assess clindamycin impact on SSI prevention in clean craniotomy. METHODS: A retrospective analysis was conducted using a prospective surveillance database focused on SSI and antibiotic prophylaxis monitoring. Patients who underwent clean craniotomy between 2005 and 2020 were included. After univariate and multivariate analyses, we performed causal inference analysis with a propensity score matching to assess the excess risk of SSI. RESULTS: Among 12 347 patients, 93.8% received cefazolin and 6.2% clindamycin. The overall SSI rate was 2.45%. Clindamycin use significantly increased SSI risk in multivariate analysis (adjusted odds ratio adjusted: 2.52 [1.72-3.69]). The propensity score found increase of SSI rate (OR = 2.59 [1.71-3.94]) and of 90 days revision for infection (OR = 2.09 [1.23-3.54]). Other independent SSI risk factors included male sex, American Society of Anesthesiologists score ≥3, prolonged surgery, specific surgical diagnoses, and cerebrospinal fluid leakage, which was the strongest predictor (aOR = 38.51 [25.24-59.30]). The most frequently isolated pathogens were Cutibacterium acnes (28.5%) and methicillin-sensitive Staphylococcus aureus (24.5%). No significant differences were observed in bacterial distribution between antibiotic groups. CONCLUSION: Clindamycin use is associated with an increased risk of SSI in clean craniotomy. Its bacteriostatic nature, and the proven safety of cefazolin in penicillin-allergic patients support maintaining cefazolin as the preferred antibiotic for every clean craniotomy patient. The safety of modifying prophylaxis protocols should be prospectively evaluated to optimize postoperative infection prevention.