Bcl-2 expression has been evaluated immunocytochemically in a series of 33 medullary thyroid carcinomas (MTC) with long-term (mean, 10.3 years) follow-up. Twenty-six of 33 cases showed intense bcl-2 immunoreactivity in more than 25% neoplastic cells. Bcl-2 immunoreactivity did not correlate with several clinicopathologic parameters including sex and age of the patients, sporadic or familial disease, tumor size and stage, amount of amyloid stroma, and immunoreactivity for calcitonin, chromogranin A, proliferating cell nuclear antigen (PCNA), N-myc, and p53. Lack of bcl-2 immunoreactivity, however, correlated significantly (P = .0001) with a shorter survival. Indeed, the seven patients with tumors devoid of bcl-2 immunoreactivity all died of disease within 8 years from the diagnosis. In multivariate analysis, lack of bcl-2 immunoreactivity was an independent predictor of worse prognosis (P = .001 for disease-free survival and P = .0001 for overall survival). None of the other clinicopathologic variable investigated proved to be an independent prognostic parameter. It is concluded that down-regulation of bcl-2 expression in MTC may identify a subset of tumors with a more aggressive clinical course.