Lessons learned during 1,701 clinical uses of HBOC-201, a polymerized bovine hemoglobin-based oxygen carrier (HBOC), were identified to provide management lessons and training material for future clinical trials and use. HBOC-201 contains 13 g/dL hemoglobin (Hb), is iso-oncotic, stable at 2°C to 30°C with shelf-life of 3 years, requires no cross-matching with half-life of 19 h, and plasma volume distribution. Adverse effects include increased blood pressure, oliguria, gastrointestinal (GI) symptoms, yellow skin and scleral discoloration, decreased pulse oximetry measurements, and transient increases in methemoglobin, hepatic, and pancreatic enzymes. There was no cardiotoxicity. Elevations in blood pressure were transient and were managed with vasodilators. Oliguria was of limited duration. GI symptoms were treated with smooth muscle relaxants. Yellow skin and sclera were self-limiting, caused by Hb metabolism. The most important clinical management errors were lack of understanding of volume expansion effects and the half-life properties of HBOC-201, and failure to repeat infusions. Early use of HBOC-201 for Expanded Access when Hb less than 5 g/dL optimized survival and minimized advanced resource utilization. For phase 3 trials, there was transfusion avoidance of 96% for 24 h, 70% for 1 week, with no difference in serious adverse events or mortality whether patients received at most 10 bags HBOC-201 or at most 3 units blood. More nonserious events occurred with HBOC-201. Age, history of cardiac disease, and Hb deficit, but not randomization to HBOC-201, were significantly predictive of cardiac ischemic events. Administration of HBOC-201 in1,701 humans showed it was well tolerated in a wide range of doses and clinical settings. HBOC-201 should be considered when blood is not available or an option.