Poorly differentiated carcinoma of the thyroid gland (PDC) represents an heterogeneous group of epithelial neoplasms with morphologic features and clinical characteristics intermediate between well differentiated and anaplastic (undifferentiated) carcinomas. Unlike well differentiated tumors, PDCs are associated with significant morbidity and mortality. The general prevalence of RET/PTC rearrangement in thyroid PDC and its impact on patient outcome are unknown. To address these issues and to identify prognostically relevant clinicopathologic parameters, we have investigated a series of 62 PDCs. RET/PTC rearrangement, analyzed by RT-PCR and immunohistochemistry using antibodies specific for the tyrosine kinase and juxtamembrane portions of the RET protein, was identified in 8/62 (12.9%) PDCs. RET/PTC was more common in cases with histologic evidence indicating coexistence with or possible evolution from a well differentiated papillary carcinoma (5 of 25 tumors, 20%) but did not correlate with other clinicopathologic parameters. The relatively low prevalence of RET activation in PDCs argues against a major role for RET/PTC in the progression from well to poorly differentiated thyroid tumor phenotypes. Survival analysis demonstrates that poor survival in PDC is associated with old age, male sex, invasion of extrathyroidal soft tissues, coexistence in the same tumor of oncocytic features with insular growth pattern, and distant metastases but not RET activation.