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BACKGROUND Severe hypocalcemia (SH) is a dreaded complication of total parathyroidectomy (TPTX) without auto-transplantation. AIM To compare conventional and preventive calcium supplementation (CS) regimens in terms of SH occurrence after TPTX. METHODS This retrospective study included patients who underwent TPTX between January 2015 and May 2018 at the China-Japan Friendship Hospital. From January 2015 to May 2016, conventional CS was performed in patients who underwent TPTX, with calcium amounts adjusted according to postoperative serum calcium levels. From October 2016 to May 2018, preventive CS was performed according to preoperative alkaline phosphatase (ALP) levels. The patients were defined as low-risk (ALP < 500 U/L) and high-risk (ALP > 500 U/L) for SH. All preoperative blood samples were collected in the fasting state on the day before surgery. Postoperative blood samples were obtained at 6-7 AM from the first postoperative day. RESULTS A total of 271 patients were included. These patients were 47.7 ± 11.1 years old, and 57.6% were male. Their mean body mass index (BMI) was 22.9 ± 3.8 kg/m2. There were no significant differences in sex, age, BMI, preoperative ALP, serum calcium, serum phosphorus, calcium-phosphorus ratio, and intact parathyroid hormone (iPTH) between the two CS groups. Compared with conventional CS, preventive CS led to lower occurrence rates of hypocalcemia within 48 h (46.0% vs 74.5%, P < 0.001) and SH (31.7% vs 64.1%, P < 0.001). Multivariable analysis showed that preoperative iPTH levels [odds ratio (OR) = 1.001, 95% confidence interval (CI): 1.000-1.001, P = 0.009), preoperative ALP amounts (OR = 1.002, 95%CI: 1.001-1.003, P = 0.002), preoperative serum phosphorus levels (OR = 8.729, 95%CI: 1.518-50.216, P = 0.015) and preventive CS (OR = 0.132, 95%CI: 0.067-0.261, P < 0.001) were independently associated with SH. In patients with preoperative ALP ≥ 500 U/L, only preventive CS (OR = 0.147, 95%CI: 0.038-0.562. P = 0.005) was independently associated with SH. CONCLUSION This study suggests that preventive CS could reduce the occurrence of SH, indicating its critical value for hypocalcemia after TPTX.