BACKGROUND Drug-refractory secondary hyperparathyroidism (SHPT) is the most common complication in patients with chronic renal failure (CRF). Although surgery is the most effective and safe method for drug-refractory SHPT, the condition may persist or recur after the primary surgery, and reoperation is often required in these patients. The purpose of our current study was to evaluate the safety and effectiveness of reoperation for drug-refractory SHPT. METHODS The clinical data of 15 patients requiring reoperation after a surgery for drug-refractory SHPT in our hospital from 2010 to 2019 were retrospectively analyzed. Changes in biochemical markers including intact parathyroid hormone (iPTH), blood calcium (Ca), blood phosphorus (P), alkaline phosphatase (ALP), and blood calcium phosphorus product (Ca*P) were compared before and after the surgery, and the effectiveness and complications of the reoperation were summarized. RESULTS The reoperation was successful in all the 15 patients after a single attempt. Routine pathological examinations identified a total of 25 parathyroid glands, of which 10 were in the neck in situ, 5 were ectopic in the neck, and 10 were in the forearm. The ectopic parathyroid glands were located inside the thyroid gland (n=1), anterior superior mediastinum (n=1), or thymus (n=3). Surgical treatment significantly improved clinical symptoms such as skin pruritus and bone pain. Blood iPTH, Ca, P, ALP, and Ca*P were significantly reduced (P<0.05 or P<0.01) after surgery. Hypothyroidism occurred in 1 patient; 4 patients undergoing orthotopic neck surgery developed transient hoarseness, which were alleviated within 6 months; no severe complications such as bleeding or death were noted. No recurrence occurred during the 6-month follow-up. CONCLUSIONS Reoperation is safe and effective for drug-refractory SHPT. Preoperative imaging should be performed to achieve accurate positioning, and the recurrent laryngeal nerve should be closely monitored during surgery. The purpose of the reoperation is to remove all possible parathyroid tissues to avoid recurrence.