Background <p>Pretherapeutic sex-specific basal calcitonin (bCt) cutoff levels and intraoperative diagnosis of desmoplastic stroma reaction (DSR) by frozen section independently facilitate the prediction of lymph-node metastases (LNM) and long-term outcomes in patients with medullary thyroid cancer (MTC). The relevance of combining these two parameters to “tailor” lymph-node (LN) surgery has thus far not been analyzed.</p> Patients and Methods <p>This single-center analysis included 306 patients covered by a calcitonin screening program. A uniform surgical protocol [thyroidectomy, bilateral central neck dissection (CND), lateral neck dissection (LND)] was applied. Risk groups were subdivided on the basis of predefined bCt cutoffs (“minimal risk,” “low risk,” and “high risk”), and the intraoperative classification of DSR was correlated with LN involvement in each patient. Biochemical long-term outcomes (mean follow-up: 8.3 years) were documented with the endpoints “disease-free,” “persistent,” or “recurrent” disease.</p> Results <p>Patients in the “minimal risk” group (37.6%) and “low risk” group (16.3%) showed central but never lateral LNM in 2.6% and 6.0% of patients, respectively (cure rate: 98.2%). In the “high risk” group (46.1%), LNM (central and/or lateral) were found in 51.1% of the patients (cure rate: 60.9%). In all risk groups, DSR negativity (overall 20.6%) confirmed absence of LNM (cure rate:100%).</p> Conclusions <p>The analysis facilitates the recommendation to individualize the extent of LND combining pretherapeutic bCt and the presence of DSR. Independent of bCt levels (risk groups), LND can be avoided following thyroidectomy in patients with DSR-negative tumors. Patients with DSR-positive tumors should undergo thyroidectomy and bilateral CND. In addition, in “high risk” patients, unilateral LND is recommended in those with bCt &lt; 350 pg/mL. Bilateral LND should be discussed in patients with M0 status and bCt &gt; 350 pg/mL.</p>