OBJECTIVES: Peginesatide is a peptide-based erythropoietin receptor agonist withdrawn after anaphylaxis/hypotension events (AHEs) occurred in 2012 and 2013.  Centers affiliated with a phase IV study conducted by the largest dialysis organization (LDO) in the United States treated 20,000 patients and unaffiliated centers treated 5,000 patients. Our objective was to summarize AHEs associated with peginesatide during the phase IV study. METHODS: The pilot included manufacturer-supplied nurse monitors at 10 LDO sites who prospectively evaluated efficacy, safety, and logistics of peginesatide.  Interim analyses in January 2013 were favorable. A protocol change in October required that no other intravenous medication be administered within one hour of peginesatide, after 8 anaphylaxis hypotension events from the pilot occurred. The pilot was expanded to 348 of the LDO’s 2100 sites.  Centers unaffiliated with the pilot also provided peginesatide without monitoring.  We compared timeliness, quantity, and characteristics of anaphylaxis-hypotension events from each setting. RESULTS: Twenty eight AHEs were from the phase IV study (1.4 per 1,000 patients) and 10 were from unaffiliated centers (1.4 per 1,000 patients). Centers in the pilot reported events more rapidly (median days = 46 versus 81).  Minutes to onset was similar (median = 3 versus 5). AHEs from the pilot were more often grade 4 severity or fatal (44% versus 10%) or associated with cardiorespiratory arrest (29% versus 0%). On February 11 and 12, 2013, three fatalities and two grade IV events occurred at four pilot sites. An unplanned analysis identified a fatality rate of 0.3/1000-treated patients in the pilot study. Peginesatide was withdrawn. CONCLUSIONS: Absent timely and comprehensive conduct of the LDOs pilot study , the safety signal may have gone unnoticed for years. Prospectively-monitored phase IV studies could enhance detection of rare serious adverse events of novel medicines, including biologicals.