Because of recent literature reports of the rare occurrence of osteomyelitis in patients with sickle cell disease, we reviewed 5 years of experience at Dhahran Health Center (Dhahran, Saudi Arabia). Twelve cases of bone and/or joint infection were identified in patients with sickle cell disease; 83% caused by Salmonella species. This relatively high incidence might be related to the common occurrence of infection with Salmonella in this region. Long bone and multiple site involvements were noticed. Differentiation from acute bone infarcts is difficult, and a systemic and aggressive approach to early diagnosis, management, and follow-up is suggested. Before therapy is started, full history, physical examination, blood cultures, local cultures, stool and urine cultures, and measurement of febrile agglutinin levels should be done. Once diagnosis is confirmed or highly suspected, adequate surgical drainage, prolonged parenteral antibiotic therapy, and transfusion of packed red blood cells should be used. A prolonged follow-up is recommended.