BACKGROUND Hypocalcemia is the most common complication following total thyroidectomy. This study aimed to evaluate the efficacy of perioperative combined calcium and vitamin D supplementation compared to postoperative combined calcium and vitamin D supplementation in reducing symptomatic hypocalcemia. METHODS A prospective randomized placebo-controlled trial was carried out in patients undergoing total or completion thyroidectomy from June 2017 to May 2022. Eligible patients were assigned to receive either calcium carbonate and alfacalcidol or placebo 3 days before surgery, and both groups were given calcium carbonate and alfacalcidol for 14 days after surgery. Clinical outcomes (signs and symptoms of hypocalcemia, requirement of intravenous calcium, and medication-induced hypercalcemia) and laboratory results (calcium and parathyroid hormone levels) were compared between the two groups. RESULTS One hundred and thirty-four patients were included in the analysis, 68 were in perioperative oral calcium and vitamin D supplementation group, and 66 were in postoperative oral calcium and vitamin D supplementation group. Symptomatic hypocalcemia rates were significantly lower in the perioperative group than in the postoperative group (8.8 and 22.7%, respectively, P=0.033). All symptomatic hypocalcemia cases in the perioperative group occurred in the first 24 hours after surgery. Mean calcium levels were significantly higher in the perioperative group at 24 and 48 hours after surgery. Intravenous calcium requirement rate was lower in the perioperative group but the difference was insignificant (2.9 and 12.1%, P=0.053). Mean parathyroid hormone levels were within the normal range and did not differ between groups. No medication-induced hypercalcemia was detected in either group. CONCLUSIONS Perioperative oral calcium and vitamin D supplementation significantly decreased the risks of symptomatic and biochemical hypocalcemia compared to postoperative oral calcium and vitamin D supplementation. The perioperative supplementation also shortened the recovery period of symptomatic hypocalcemia to within 24 hours.