Prognostic significance of nondiploid DNA determined by flow cytometry in sporadic and familial medullary thyroid carcinoma. To clarify the role of DNA measurements in predicting outcome after surgical treatment of medullary thyroid carcinoma (MTC), we performed flow cytometric analysis in nuclear suspensions of 119 MTC tumors. Of the 119 patients, 63 (53%) patients had sporadic tumors and 56 (47%) patients had familial tumors; survivors were followed for a mean of 13 years. DNA content was normal in 92 (77%) patients and abnormal (nondiploid) in 27 (23%) patients. Ten-year cause-specific mortality rates were 12%, 42%, and 49% with diploid, tetraploid/polyploid, or aneuploid tumors (p = 0.0009) and were greater with nondiploid tumors both in the sporadic (p = 0.012) and multiple endocrine neoplasia (familial) cases (p = 0.114). None of 27 patients with TNM stage I disease died of MTC. In patients with TNM stages II, III, and IV disease, DNA nondiploid tumors were associated with increased deaths from MTC. In a Cox proportional hazards model involving all 119 patients and adjusted for disease stage and inheritance pattern, nondiploid DNA was independently associated with increased deaths from MTC (p = 0.008). In an identical Cox model restricted to the 92 DNA diploid tumors, an S-phase fraction of 15.0% or more remained a significant variable (p = 0.034) after adjustment for stage and inheritance pattern. We therefore conclude that DNA measurements do have a role to play in predicting outcome after surgical treatment of MTC. 