To evaluate surgical complications, patterns of lymph node metastases, and calcitonin response to compartment-oriented lymphadenectomy in patients with primary or recurrent medullary thyroid carcinoma (MTC). The majority of patients with invasive MTC have metastasis to regional lymph nodes at the time of diagnosis, as evidenced by the frequent finding of persistently elevated calcitonin levels after thyroidectomy and the high rates of recurrence in the cervical lymph nodes reported in retrospective studies. These data have provided the rationale for surgeons to perform a more extensive lymphadenectomy at the time of initial thyroidectomy and to consider reoperative cervical lymphadenectomy in patients with persistently elevated calcitonin levels after thyroidectomy. Forty patients underwent surgery for MTC from 1991 to 1997 (23 sporadic cases, 17 familial cases). Patients were divided into three groups based on whether they had undergone previous thyroidectomy and on the results of standardized staging studies performed after referral to the authors' institution. Group 1 (11 patients) had received no previous surgery; group 2 (13) underwent thyroidectomy before referral and had an elevated calcitonin level without radiologic evidence of local regional or distant metastases; and group 3 (16) underwent thyroidectomy before referral and had an elevated calcitonin level with radiologic evidence of local-regional recurrence. The central neck compartment was dissected in all patients; preoperative staging and the extent of previous surgery dictated the need for lateral (modified radical) neck dissection. After primary or reoperative surgery, calcitonin levels were assessed. All patients had major reductions in postoperative calcitonin levels. Seven (29%) of 24 patients in groups 1 and 2 achieved normal calcitonin values compared with only 1 (6%) of 16 in group 3. Postoperative complications included seven cases (17%) of permanent hypoparathyroidism; five (71%) of these occurred in group 3. There were no iatrogenic recurrent laryngeal nerve injuries; one patient required recurrent nerve resection to achieve complete tumor extirpation. At a median follow up of 35 months, local recurrence was documented in 5 (13%) of 40 patients. Compartment-oriented lymphadenectomy performed early in the course of MTC is safe and may return calcitonin levels to normal in up to 25% of carefully selected patients. However, reoperation for bulky cervical disease (group 3) rarely results in normal calcitonin levels and is associated with a high incidence of permanent hypoparathyroidism.