OBJECTIVE Craniectomy is often performed to decrease intracranial pressure following trauma and vascular injuries. The subsequent cranioplasty procedures may be complicated by surgical site infections (SSIs) due to prior trauma, foreign implants, and multiple surgeries through a common incision. Several studies have found that intrawound vancomycin powder (VP) is associated with decreased risk of SSIs after spine operations. However, no previously published study has evaluated the effectiveness of VP in cranioplasty procedures. The purpose of this study was to determine whether intrawound VP is associated with decreased risk of SSIs, to evaluate VP's safety, and to identify risk factors for SSIs after cranioplasty among patients undergoing first-time cranioplasty. METHODS The authors conducted a retrospective cohort study of adult patients undergoing first-time cranioplasty for indications other than infections from January 1, 2008, to July 31, 2014, at an academic health center. Data on demographics, possible risk factors for SSIs, and treatment with VP were collected from the patients' electronic health records. RESULTS During the study period, 258 patients underwent first-time cranioplasties, and 15 (5.8%) of these patients acquired SSIs. Ninety-two patients (35.7%) received intrawound VP (VP group) and 166 (64.3%) did not (no-VP group). Patients in the VP group and the no-VP group were similar with respect to age, sex, smoking history, body mass index, and SSI rates (VP group 6.5%, no-VP group 5.4%, p = 0.72). Patients in the VP group were less likely than those in the no-VP group to have undergone craniectomy for tumors and were more likely to have an American Society of Anesthesiologists physical status score > 2. Intrawound VP was not associated with other postoperative complications. Risk factors for SSI from the bivariable analyses were diabetes (odds ratio [OR] 3.65, 95% CI 1.07-12.44), multiple craniotomy procedures before the cranioplasty (OR 4.39, 95% CI 1.47-13.18), prior same-side craniotomy (OR 4.73, 95% CI 1.57-14.24), and prosthetic implants (OR 4.51, 95% CI 1.40-14.59). The multivariable analysis identified prior same-side craniotomy (OR 3.37, 95% CI 1.06-10.79) and prosthetic implants (OR 3.93, 95% CI 1.15-13.40) as significant risk factors for SSIs. After adjusting for potential confounders, patients with SSIs were more likely than those without SSIs to be readmitted (OR 7.28, 95% CI 2.07-25.60). CONCLUSIONS In this study, intrawound VP was not associated with a decreased risk of SSIs or with an increased risk of complications. Prior same-side craniotomy and prosthetic implants were risk factors for SSI after first-time cranioplasty.