Previous studies have suggested that thyroid nodules found in patients with Graves' disease (GD) have a higher likelihood of being malignant, and that thyroid cancer behaves more aggressively when associated with GD, although both of these assertions remain controversial. The purpose of this study was to assess the frequency of cold scintiscan (SC) defects in patients with GD, and to determine the prevalence of thyroid cancer in such patients. Our secondary objective was to determine if there are any risk factors for developing cold defects by comparing clinical characteristics of both GD patients with cold SC defects and age and gender-matched GD patients without cold defects. We included in this analysis patients with a confirmed diagnosis of GD for whom SC results and adequate follow-up information were available. Clinic records were available in 772 patients with GD. Of these, 325 patients met eligibility criteria. Cold defects were found in 39 of 325 (12.0%) patients. Among these, 22 (56.4%) were referred for surgery, of whom 6 (1.85% of all GD patients, 15.2% of GD patients with cold nodules, 25% of GD patients with palpable nodules, and 27.3% of those undergoing surgery) had papillary thyroid cancer (PTC) in the location corresponding to the SC defect. In 2 PTC patients, no palpable abnormality corresponded to the cold defect found to contain cancer at surgery. One PTC patient was found to have metastatic disease to bone, and 2 additional PTC patients required multiple therapies with radioiodine. Compared to age and gender-matched control patients with GD and without cold SC defects, there were no differences in radioactive iodine uptake (RAIU), goiter size, duration of disease, degree of elevation in microsomal antibody (MA) titers, or thyroid-stimulating immunoglobulin (TSI). We conclude that thyroid scintigraphy is an important preliminary test in the evaluation of patients with GD, and that the prevalence of thyroid cancer in the location corresponding to a focal cold SC defect provides justification for further diagnostic evaluation or surgical management.