Clinical, biochemical, and morphologic parameters in 72 patients with familial medullary thyroid carcinoma (MTC) associated with multiple endocrine neoplasia IIA (MEN IIA) were reviewed. Sixty-nine patients had undergone total thyroid resection. In 27 patients (Group I) the thyroid tumors were smaller than 0.7 cm in diameter; five of these patients had C-cell hyperplasia alone. In 19 patients (Group II) tumors ranged from 0.7 to 1.5 cm, and in 26 patients (Group III) they were larger than 1.5 cm. The mean ages at surgery were 19.6 years (Group I), 33.7 years (Group II), and 32.2 years (Group III). Regional lymph node metastases occurred less often in patients of Group I, 4/20 (20%) and Group II, 4/13 (30%) than in those of Group III, 14/17 (82%) [p = 0.0001]. Elevated postoperative plasma calcitonin levels, indicative of residual MTC, were observed less frequently in patients in Group I, 6/27 (22%) and Group II, 6/15 (50%) than in Group III, 11/15 (73%) [p = 0.005]. All of the patients in Group I and Group II are alive (mean follow-up of 3.5 years and 6.0 years following surgery), whereas 6/26 (23%) Group III patients have died of metastatic MTC, three within 2 years of initial diagnosis. Histologic features varied with tumor diameter. All tumors from patients in Group III contained amyloid, while the majority of those from patients in Group I had an infiltrative configuration and 9/22 tumors lacked amyloid. Among neoplasms from patients in Group III, mitotic figures correlated with distant metastases or death from tumor. Only 1/16 patients who died from MTC had a distinctive tumor morphology, namely a prominent component of small cell anaplastic carcinoma. Early detection of minimal MTC in MEN IIA family members offers the best chance of curing patients with this potentially fatal lesion.