Twenty-three patients with a benign bone lesion grafted with calcium sulfate, with and without demineralized bone matrix, were reviewed. At a minimum of 1 year postoperatively, 21 patients had achieved between 76% and 100% bone repair based on anteroposterior and lateral radiographs. Overall, the mean Enneking Functional Evaluation System score was 98%. Calcium sulfate is a well-tolerated, biodegradable, osteoconductive bone graft substitute. It is a reasonable alternative to autogenous bone graft for benign bone lesions.