Repeat episodes of musculoskeletal infarction coupled with immunosuppression predispose sickle cell patients to infectious complications throughout their lives. Osteomyelitis is a familiar complication of sickle cell disease, and it may result in significant morbidity, especially when occurring in multiple sites. Staphylococcus and Salmonella remain the most common causes of osteomyelitis in sickle cell patients. Vancomycin-resistant enterococcus (VRE) infections have been reported mainly in connection with bacteremias and infections outside of the musculoskeletal system. To our knowledge, only a few cases of VRE long bone osteomyelitis have been reported in the literature. A few antimicrobial agents are available to treat VRE infections. The occurrence of VRE osteomyelitis is a major clinical concern, especially in an immunocompromised host, such as a sickle cell patient. We present a case of multiple long bone vancomycin-resistant Enterococcus faecium (mixed organisms) osteomyelitis in a sickle cell patient, and we report on a new method of using quinupristin-dalfopristin as part of the management plan to treat a complicated VRE infection successfully. We discuss the mechanism of action of anti-VRE drugs and the future direction to combat VRE in orthopedic infections.