The effect of parathyroid hormone (PTH) on the production of osteoprotegerin (OPG) remains controversial. Most in vitro studies indicate that PTH decreases OPG secretion by the osteoblast, but in vivo observations are conflicting. In primary hyperparathyroidism (PHPT), hypersecretion of PTH leads to enhanced bone resorption and formation with increased risk of fracture. Patients with PHPT are cured by surgery, resulting in normalization of PTH levels and bone metabolism, but the concomitant effects on OPG production are not known. The hypothesis of the present study was that the circulating level of OPG is diminished in patients with PHPT and increases with successful parathyroidectomy. We also speculated that serum OPG may determine the magnitude of bone loss up to the time of surgery. In the present study, 20 patients (17 women and 3 men, mean age 62 y) with PHPT who were candidates for surgical cure were examined before and 12 months after surgery. Bone turnover markers decreased and BMD increased significantly after surgery. Serum OPG did not correlate with PTH before surgery (r = 0.07, P = 0.77) and was not affected by parathyroidectomy (P = 0.79). After normalization of PTH, bone formation markers showed significant (P1NP) and near-significant (osteocalcin) correlations with serum OPG. In conclusion, serum OPG is not decreased in patients with PHPT, nor is serum OPG to any demonstrable extent regulated by PTH pre- or postoperatively.