Refolding of the soluble recombinant binding-active extracellular domain of the murine erythropoietin receptor (sEPO-R) was achieved with greater than 90% recovery either from urea/NaCI (1.5/0.5 M) or guanidine HCI (1 M). An expression plasmid encoding the extracellular plasma region of the human EPO-R (sEPO-R) was transfected into COS cells, and the sEPO-R so produced was labelled with [35S]methionine and purified by EPO-affinity chromatography on a EAH-Sepharose 4B-EPO column. Rapid rates of refolding were required for recovery of the native proteins. Refolding was evaluated by rebinding of the sEPO-R to the EPO affinity column.