The aim of the study was to determine severe hypocalcemia rate following thyroidectomy and factors associated with its occurrence.Hypocalcemia is the most common complication after thyroidectomy. Severe post-thyroidectomy hypocalcemia can be life-threatening; data on this specific complication are scarce.Patients who underwent thyroidectomy in the American College of Surgeons-National Surgical Quality Improvement Program thyroidectomy-targeted database (2016-2017) were abstracted. A severe hypocalcemic event was defined as hypocalcemia requiring intravenous calcium, emergent clinic/hospital visit, or a readmission for hypocalcemia. Multivariable regression was used to identify factors independently associated with occurrence of severe hypocalcemia.Severe hypocalcemia occurred in 5.8% (n = 428) of 7366 thyroidectomy patients, with 83.2% necessitating intravenous calcium treatment. Rate of severe hypocalcemia varied by diagnosis and procedure (0.5% for subtotal thyroidectomy to 12.5% for thyroidectomy involving neck dissections). Overall, 38.3% of severe hypocalcemic events occurred after discharge; in this subset, 59.1% experienced severe hypocalcemia despite being discharged with calcium and vitamin D. Severe hypocalcemia patients had higher rates of recurrent laryngeal nerve injury (13.4% vs 6.6%), unplanned reoperations (4.4% vs 1.3%), and longer hospital stay (30.4% vs 6.2% ≥3 days (all P < 0.01). After multivariate adjustment, severe hypocalcemia was associated with multiple factors including Graves disease [odds ratio (OR) = 2.06], lateral neck dissections (OR: 3.10), and unexpected reoperations (OR = 3.55); all P values less than 0.01.Severe hypocalcemia and suboptimal hypocalcemia management after thyroidectomy are common. Patients who experienced severe hypocalcemia had higher rates of nerve injury and unexpected reoperations, indicating surgical complexity and provider inexperience. More biochemical surveillance particularly a parathyroid hormone-based protocol, fine-tuned supplementation, and selective referral could reduce occurrence of this morbid complication.