The natural history and prognostic factors of medullary carcinoma of the thyroid (MCT) were studied in 161 patients seen at the University of Texas M. D. Anderson Hospital and Tumor Institute at Houston between 1944 and 1983. One hundred twenty-five patients (77.6%) had the sporadic variety of MCT, 31 patients (19.3%) had multiple endocrine neoplasm (MEN) type IIa and 5 patients (3.1%) had MEN-IIb. The disease occurred equally in both sexes (M:F ratio 1:1.05). Thyroid nodules were the most common presenting feature especially in patients with the sporadic disease and MEN-IIb. Fifteen patients with MEN-IIa had occult MCT; the diagnosis was made through screening of family members with calcitonin measurement before and after stimulation with calcium or pentagastrin. Sixteen patients with MEN-II had pheochromocytoma and 7 had hyperparathyroidism. Total thyroidectomy was the most commonly performed operation. The lowest incidence of recurrence occurred in patients who underwent total thyroidectomy and modified neck dissection. Radioactive 131I was used as adjunct to surgery in 19 patients but it did not improve the survival or lower the incidence of recurrence. Patients who received postoperative radiotherapy had significantly lower adjusted survival rates than those treated by surgery alone, but we tended to irradiate patients with more advanced disease. Chemotherapy was administered to 11 patients with disseminated metastases but the response was poor. The 5- and 10-year adjusted survival rates of all the patients with MCT were 78.2% and 61.4%, respectively. Patients with MEN-IIa had much better rates than patients with sporadic disease (p = 0.0005), who were 7.74 times more likely to die of MCT. The stage of the disease at presentation was a major prognostic factor. Patients with stages III or IV disease were 7.31 times more likely to die of MCT than those with stages I or II. There was no significant difference in survival between patients with stages I and II or III and IV. The presence of cervical lymph node metastases did not affect the survival adversely. Direct extension with involvement of tissue was a bad prognostic sign. Patients younger than 40 years old at the time of diagnosis of MCT had a significantly better adjusted survival rate than those who were older. Women had a better prognosis than men, who were 1.89 times more likely to die of MCT. Diarrhea was a bad prognostic sign. However, it occurred more frequently in patients with advanced stages of the disease and larger tumor mass.(ABSTRACT TRUNCATED AT 400 WORDS)