Primary as well as secondary hyperparathyroidism may be associated with anemia, and parathyroidectomy (PTx) may improve or even heal it. The precise link between the two conditions is still matter of discussion. The purpose of the present study was to investigate possible effects of PTx on serum immunoreactive erythropoietin (iEPO) in secondary (group I, n = 23), and primary (group II, n = 16) hyperparathyroidism patients, and in 3 patients undergoing cervicotomy for thyroid mass removal (group III). In group I patients, circulating iEPO levels rose from 23.1 +/- 4.8 mU/ml before PTx to 28.2 +/- 5.0 and 245 +/- 125 mU/ml (mean +/- SEM) at day 7 (p = NS) and 14 after PTx (p less than 0.003), respectively. Reticulocyte count increased 2 weeks after PTx: from 61,000 +/- 13,317 to 86,533 +/- 13,462/mm3 (p less than 0.05, n = 23). In 4 of these patients serum iEPO levels could be measured again 12-24 months after PTx. They were slightly higher than those determined before PTx: 37.0 +/- 8.4 versus 31.8 +/- 13.5 mU/ml. Their hematocrits were also higher than before PTx: 12.8 +/- 0.9 versus 11.0 +/- 0.9 g/dl. In group II patients, serum iEPO levels remained unchanged after PTx: 17.5 +/- 2.0 mU/ml before PTx and 20.0 +/- 3.0 mU/ml 14 days PTx. The reticulocyte count, however, increased significantly 2 weeks after PTx: from 25,103 +/- 3,000 to 40,827 +/- 4,080/mm3 (p less than 0.01). In group III patients, serum iEPO, reticulocyte count, and hemoglobin remained stable after surgery. Since all group I patients had received vitamin D supplementation after PTx, we studied an additional group of 14 chronic dialysis patients (group IV) who received either calcitriol (1 micrograms/day, n = 7) or placebo (n = 7) during 14 days. The patients on calcitriol treatment, but not those on placebo, had a significant decrease of serum iEPO: 18.6 +/- 4.9 versus 16.0 +/- 4.2 mU/ml (p less than 0.03). In conclusion, PTx led to a striking increase of serum iEPO and blood reticulocytes in uremic patients with secondary hyperparathyroidism, and an increase of reticulocyte count, but not of iEPO, in patients with primary hyperparathyroidism. Marked changes of circulating PTH, extra-or intracellular calcium and phosphorus concentrations as well as of tissue sensitivity to EPO after PTx could all be responsible. In contrast, the surgical procedure and the therapeutic increase in plasma calcitriol do not appear to be involved.