This article presents our experience with the use of antibiotic-impregnated calcium sulfate in the management of comminuted open fractures with a bony defect caused by combat-related blast injuries and high-energy wounds. Calcium sulfate was used 19 times in 15 patients (17 fractures) as a bone graft substitute and a carrier for antibiotics. The anatomic sites of the graft were as follows: 6 calcanei, 1 midfoot, 1 metatarsal, 5 tibiae, 3 femorae, and 1 humerus. The average number of procedures prior to grafting was 6.2 (range, 2-10; median, 6) with grafting performed at an average 28 days after injury (range, 9-194 days; median, 14 days). Average radiographic follow-up of 12 fractures not requiring repeat grafting or amputation was 8.5 months (range 1-19 months; median, 7 months), and all of these fractures demonstrated clinical and radiographic evidence of fracture healing and consolidation. Four patients subsequently underwent 5 transtibial amputations: 2 for persistent infection, 1 when the patient changed his mind against limb salvage acutely, and 2 for severe neurogenic pain. Including the 2 amputations for persistent infection, 4 patients (22.2%) required further surgical management of infection. Three patients (17.6%) subsequently developed heterotopic ossification at the graft site, which required surgical excision. Antibiotic-impregnated calcium sulfate is effective in treating severe, contaminated open fractures by reducing infection and assisting with fracture union.