We studied the in vitro culture growth of bone marrow and blood erythroid progenitors and serum erythropoietin (EPO) levels by radioimmunoassay in 24 patients with idiopathic erythrocytosis (IE). All patients had an increased red blood cell (RBC) mass and lacked a cause of secondary polycythemia, but did not fulfill the diagnostic criteria of polycythemia vera (PV). Marrow and blood cultures were obtained simultaneously; the results of endogenous (EPO-independent) erythroid colony (EEC) growth were parallel in both cultures. EECs were present in five patients, all of them developed PV 3 to 48 months later. The EEC number did not correlate with the time to the progression of PV. In contrast, none of the 19 EEC-negative patients had PV evolution during a median follow-up period of 38 months. Three of the five IE patients in whom EECs formed displayed vascular complications during their clinical course compared with three of 19 patients who did not have EEC. The serum EPO levels were variable: low in five, normal in 14, and high in five patients. Serial measurements of serum EPO levels in three of five patients who had high initial levels showed persistently elevated values; the underlying cause of the increased EPO production could not be defined during a follow-up period of more than 36 months. Of the five patients who subsequently developed PV, two had low serum EPO levels and three had normal values at initial evaluation. Serum EPO levels did not correlate with the occurrence of thrombotic complications. Our results show that serum EPO levels have limited value in determining the underlying cause of IE and cannot predict the clinical course of patients with IE, whereas the assessment of EEC in bone marrow or blood can identify IE patients who will have PV evolution.