Introduction Currently, there is no consensus on the indication of prophylactic surgery of the nodal compartments in the treatment of medullary thyroid carcinoma (MTC). The aim of our study was to perform a correlation study between preoperative calcitonin (basalCT) values and lymph node involvement to establish a criterion on which to base prophylactic surgery in these patients. Material and Methods We conducted an observational, retrospective and multicentre study with 29 hospitals. Patients over 18 years of age with a diagnosis of MTC with a pre-surgical calcitonin registry were included. The minimum surgery in all patients had to have been total thyroidectomy (TT) with central compartment lymph node dissection (CCLND). Receiver operating characteristic (ROC) curve analysis was used to establish basalCT cut-off values as predictors of postoperative lymph node involvement. Results A total of 244 patients were included. Baseline calcitonin (basalCT) was a good predictor of nodal involvement (AUC 0.718 and 95%CI 0.66–0.978). Heritability was identified as a preoperative factor correlated with baseline tumour CT values ( p  = 0.000). With a probability of lymph node involvement below 10%, new cut-off points were established. A prophylactic bilateral lateral lymph node dissection in sporadic tumours should be performed at a basalCT > 600 pg/mL; in the case of RET-mutated tumours this value would be 200 pg/mL. Conclusion The baseline CT value is a good predictor of postoperative lymph node involvement in MTC, however, cut-off points should depent on the hereditary nature of the tumour.