Hypocalcemia is a common sequela of thyroidectomy; however, its causative factors have not been completely delineated. A prospective study of 60 patients who underwent unilateral (n = 15) or bilateral (n = 45) thyroidectomy between 1990 and 1993 was completed to determine the incidence and risk factors for hypocalcemia. Free thyroxine, thyrotropin, and alkaline phosphatase levels were obtained before operation in all patients, together with preoperative and postoperative ionized calcium, parathyroid hormone (PTH), calcitonin, and 1,25-dihydroxyvitamin D3 levels. All patients were examined for age, gender, extent of thyroidectomy, initial versus reoperative neck surgery, weight and pathologic characteristics of resected thyroid tissue, substernal thyroid extension, and parathyroid resection and autotransplantation. Hypocalcemia, defined by an ionized calcium level less than 4.5 mg/dl, occurred in 28 patients (47%), including nine (15%) symptomatic patients who required vitamin D and/or calcium for 2 to 6 weeks. In no patient did permanent hypoparathyroidism develop. With a multivariate logistic regression analysis, factors that were predictive of postoperative hypocalcemia included an elevated free thyroxine level (p = 0.003), cancer (p = 0.010), and substernal extension (p = 0.046). Postoperative decline in parathyroid hormone was not an independent risk factor for hypocalcemia, indicating that other factors besides parathyroid injury, ischemia, or removal are involved in the pathogenesis of postthyroidectomy hypocalcemia. An elevated free thyroxine level, substernal thyroid disease, and carcinoma are risk factors for postthyroidectomy hypocalcemia, and their presence should warrant routine postoperative calcium measurement. In the absence of these risk factors, routine postoperative measurement of serum calcium is unnecessary.