Background. Heterotopic ossification (HO) is a known complication following total hip arthroplasty, with increased incidence in certain patient populations. Current prophylaxis options include oral non-steroidal anti-inflammatory drugs (NSAIDs) and radiation therapy, but an optimal radiation protocol has yet to be clearly defined. We performed a randomized, double-blinded clinical trial in high-risk total hip arthroplasty patients to determine the efficacy of 400 cGy versus 700 cGy doses of radiation. Methods. 147 patients at high risk for HO undergoing total hip arthroplasty (THA) at Rush-St. Luke's- Presbyterian medical center were randomized to either a single 400 cGy or 700 cGy dose of radiation. High risk was defined as diagnosis of diffuse idiopathic skeletal hyperostosis (DISH), hypertrophic osteoarthritis, ankylosing spondylitis, or history of previous heterotopic ossification. Radiation was administered over a 14 × 6 cm area of soft tissue and given on the first or second post-operative day. A blinded reviewer graded anterior-posterior (AP) and lateral radiographs taken immediately post-operatively and at a minimum of 6 months post-operatively. Progression was defined as an increase in Brooker classification from the immediate post-operative to the long-term post-operative radiograph. Operative data including surgical approach, use of cemented implants, revision surgery, and post-operative range of motion data were also collected. Results. A significantly greater portion of patients who received the 400 cGy dose demonstrated progression of HO than patients who received the 700 cGy dose. No pre-operative factors were associated with a higher rate of progression. Patients who progressed had less flexion on physical exam than patients who did not progress, but this was not clinically significant. Conclusion. To the authors' knowledge this is the largest randomized prospective study to date comparing two single-dosages of radiation treatment. 700 cGy demonstrates superiority over 400 cGy in preventing HO formation following total hip arthroplasty in high-risk patients and may be the more effective treatment in this population