Background MP4OX (oxygenated polyethylene glycol-modified hemoglobin) is an oxygen therapeutic agent with potential applications in clinical settings where targeted delivery of oxygen to ischemic tissues is required. The primary goal of this study was to investigate MP4OX for preventing hypotensive episodes. An additional goal was to establish the safety profile of MP4OX in a large surgical population. Methods Patients (n = 367) from 18 active study sites in six countries, undergoing elective primary hip arthroplasty with spinal anesthesia, were randomized to receive MP4OX or hydroxyethyl starch 130/0.4. Patients received a 250-ml dose at induction of spinal anesthesia and a second 250-ml dose if the protocol-specified trigger (predefined decrease in systolic blood pressure) was reached. The primary end point was the proportion of patients who developed one or more hypotensive episodes. Results The proportion of patients with one or more hypotensive episodes was significantly lower (P < 0.0001) in the MP4OX group (66.1%) versus controls receiving hydroxyethyl starch 130/0.4 (90.2%). More MP4OX-treated patients experienced adverse events compared with controls (72.7% vs. 61.4%; P = 0.026). Transient elevations in laboratory values (e.g., alanine aminotransferase, aspartate aminotransferase, lipase, and troponin concentrations) occurred more frequently in the MP4OX group. There were no significant differences in the incidence of serious adverse events or in the composite morbidity and ischemia outcome end points, but nausea and hypertension were reported more often in MP4OX-treated patients. Conclusion MP4OX significantly reduced the incidence of hypotensive episodes in patients undergoing hip arthroplasty, but the adverse event profile does not support use in routine low-risk surgical patients for the indication evaluated in this study.