BACKGROUND The clinical relevance of medullary thyroid microcarcinoma, a calcitonin-secreting malignancy, as a valid target for biochemical screening programs has been called into doubt. OBJECTIVE This investigation aimed at clarifying the intensity of lymphatic spread and exploring the potential for biochemical cure in medullary thyroid microcarcinoma. METHODS This was a retrospective analysis. METHODS The setting was a tertiary referral center. METHODS Included were 233 patients with hereditary (126 patients) or sporadic (107 patients) medullary thyroid microcarcinoma. METHODS The intervention was compartment-oriented surgery. METHODS Clinical-histopathological variables were stratified by primary tumor diameter (2-mm increments) and biochemical cure. RESULTS With incremental tumor diameter, increasingly more patients with medullary thyroid microcarcinoma harbored lymph node metastases: from 6 to 62% of patients (P < 0.001) for hereditary and from 13 to 43% of patients (P = 0.01) for sporadic disease. The corresponding biochemical cure rates declined from 96 to 71% (P = 0.001) and from 85 to 77% (P = 0.01). Distant disease (two instances of lung metastasis and one instance of bone and liver metastasis) was exceptional, affecting 1.3% of patients with medullary thyroid microcarcinoma. Strongest predictors of a patient's failure to achieve normal calcitonin serum levels were positive nodal status (79 vs. 11% in hereditary and 79 vs. 12% in sporadic disease; both P < 0.001) and the number of involved nodes (means of 6.6 vs. 0.3 nodes in hereditary and 8.8 vs. 0.4 nodes in sporadic disease; both P < 0.001). CONCLUSIONS Sporadic and hereditary medullary thyroid microcarcinoma carry a significant risk of lymph node metastasis and postoperative calcitonin elevation.