Background:In hereditary medullary thyroid carcinoma (HMTC), prophylactic surgery is the only curative option, which should be properly defined both in time and extent.Objectives:To identify and characterize prognostic factors associated with disease-free survival (DFS) in children from HMTC families. Design:We conducted a retrospective analysis of a multi-center cohort of 170 patients below age 21 at surgery. Demographic, clinical, genetic, biological data [basal and pentagastrine-stimulated calcitonin (CT and CT/Pg, respectively)], and tumor node metastasis (TNM) status were collected. DFS was assessed based on basal CT levels. Kaplan–Meier curves, Cox regression, and logistic regression models were used to determine factors associated with DFS and TNM staging. Results:No patients with a preoperative basal CT <31 ng/ml had persistent or recurrent disease. Medullary thyroid carcinoma defined by a diameter ≥10 mm [hazard ratio (HR): 6.0; 95% confidence interval (95% CI): 1.8–19.8] and N1 status (HR: 20.8; 95% CI: 3.9–109.8) were independently associated with DFS. Class D genotype [odds ratio (OR): 48.5, 95% CI: 10.6–225.1], preoperative basal CT >30 ng/liter (OR: 43.4, 95% CI: 5.2–359.8), and age >10 (OR: 5.5, 95% CI: 1.4–21.8) were associated with medullary thyroid carcinoma ≥10 mm. No patient with a preoperative basal CT <31 ng/ml had a N1 status. Class D genotype (OR: 48.6, 95% CI: 8.6–274.1), and age >10 (OR: 4.6, 95% CI: 1.1–19.0) were associated with N1 status. Conclusion:In HMTC patients, DFS is best predicted by TNM staging and preoperative basal CT level below 30 pg/ml. Basal CT, class D genotype, and age constitute key determinants to decide preoperatively timely surgery.