Introduction. Treatment of diabetic foot infection generally involves prolonged antibiotic therapy, surgical debridement or amputation when indicated, and management of the patient’s comorbidities. Systemic antibiotics are often prescribed when an ulcer is showing clinical signs of infection; however, treatment using systemic antibiotics alone may yield poor results. In the diabetic foot, local delivery systems have been explored to minimize systemic toxicity and eliminate concerns about antibiotic penetration while also achieving high local doses of antibiotics. Objective. This case series evaluated the clinical outcomes of a commercially pure, synthetic, antibiotic-loaded calcium sulfate for the management of diabetic foot ulcers (DFUs) complicated by osteomyelitis. Materials and Methods. A total of 106 patients requiring either major or minor debridement, amputation of 1 or more toes, forefoot amputation, or below-knee amputation received calcium sulfate combined with combinations of meropenem, colistin, or vancomycin based on antibiotic susceptibility from microbiological cultures. Results. Calcium sulfate beads were mixed with meropenem in 64 cases, colistin in 35 cases, and vancomycin in 7 cases. At final follow-up, 98 of the 106 patients (92%) had no recurrence of infection (mean follow-up, 10 weeks [range, 6–16 weeks]). No systemic adverse reactions to the local delivery of antibiotics were observed in this study. Conclusions. The use of locally released antibiotics from synthetic recrystallized calcium sulfate may offer significant benefits in the management of DFU infection compromised by poor circulation, polymicrobial growth, and associated renal and cardiac comorbidities.