Background The purpose of this study was to evaluate the efficacy of topically applied vancomycin powder in reducing the rate of surgical site infections (SSIs) in patients with diabetes mellitus (DM) undergoing foot and ankle surgery. Methods Eighty-one patients with DM who underwent reconstructive surgery of a foot and/or ankle deformity and/or trauma and who received topically applied vancomycin were matched to 81 patients with DM who did not receive topically applied vancomycin. The mean age was 60.6 years in the vancomycin group and 59.4 years in the control group (P < .05). The 2 groups were similar with regard to gender, body mass index, duration of DM, short-term and longer term glycemic control, and length of surgery. Results The overall likelihood of SSI was decreased by 73% in patients who received topically applied vancomycin (odds ratio [OR], 0.267; 95% CI, 0.089–0.803; P = .0188). The rate of superficial infection was not significantly different between the 2 groups (OR, 0.400; 95% CI, 0.078–2.062; P = .2734); however, deep infections were 80% less likely in patients who received vancomycin powder (OR, 0.200; 95% CI, 0.044–0.913; P = .0377). Conclusion High-risk diabetic patients undergoing foot and ankle surgery were notably less likely to develop an SSI with the use of topically applied vancomycin powder in the surgical wound, particularly with regard to deep infections. Topically applied vancomycin was associated with a very low rate of complications and was inexpensive ($5 per 1000 mg). Based on this study, foot and ankle surgeons may consider applying 500 to 1000 mg of vancomycin powder prior to skin closure in diabetic patients who are not allergic to vancomycin. Level of Evidence Level III, retrospective case control series.