OBJECTIVES: To determine the association between closed suction drainage and postoperative infection in patients with tibial plateau or pilon fractures. Secondarily, this study assessed if intrawound vancomycin powder modified the association of closed surgical drains with infection. METHODS: Design: Secondary analysis of the Effect of Intrawound Vancomycin Powder in Operatively Treated High-risk Tibia Fractures: A Randomized Clinical Trial (VANCO) trial. Setting: 36 academic trauma centers. Patient Selection Criteria: All patients with high-risk tibia fractures (OTA/AO classification 41B/C or 43B/C) from the VANCO trial were considered. Closed suction drains were placed based on the treating surgeon’s discretion. Patients were randomly assigned to received 1-gram intrawound vancomycin powder in the surgical wound at definitive fixation or the standard infection prevention protocol at each center. Outcome Measures and Comparisons: Deep surgical site infection (SSI) within 6 months. Comparisons were made between patients treated with and without drains. Subgroup analysis also examined the effect of drains in patients with and without intrawound vancomycin powder. RESULTS: Of the 978 study patients, 197 (20%) were treated with drains. Deep infection rates did not significantly differ between patients with or without surgical drains (8% versus 8%, p=0.88). However, intrawound vancomycin powder significantly modified the association of surgical drains on deep SSI (interaction p=0.048). Specifically, patients with drains but no vancomycin powder had the highest deep infection rate (13%; 95% CI, 6% to 19%). When vancomycin powder was used in addition to a drain, deep SSI rates were reduced by 10% (95% CI, 2% to 17%, p=0.01). CONCLUSIONS: This study suggests that closed suction drains after operative fixation of high-risk tibia fractures may not be associated with deep infection in general. However, a secondary analysis raises the possibility that drains are associated with reduced deep infection rates if topical vancomycin powder is used but associated with increased infection rates if vancomycin powder is not used. LEVEL OF EVIDENCE: Level III