BACKGROUND: Electrical impedance scanning (EIS) identifies tissue impedance changes associated with malignancy. Methods to distinguish benign from malignant thyroid nodules, particularly in patients with indeterminate cytology are lacking. PURPOSE: To determine the diagnostic accuracy of EIS in the preoperative evaluation of thyroid nodules. PATIENTS AND METHODS: From September 2002 to December 2006, 216 patients underwent thyroid fine needle aspiration (FNA) and EIS prethyroidectomy in this prospective cohort study. EIS, either positive or negative for malignancy, was correlated with final histopathology. A focal bright spot over a thyroid nodule correlating with increased conductivity and/or capacitance >25% baseline sternocleidomastoid muscle impedance defined positive EIS. Study endpoints were EIS accuracy, sensitivity (Sn), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV). This study has been registered in the National Institutes of Health's public trials registry at ClinicalTrials.gov. The registration number is NCT00571077. RESULTS: EIS correctly diagnosed 96 of 110 patients with malignant and 75 of 106 patients with benign dominant thyroid nodules: Sn = 87%, Sp = 71%, PPV = 76%, NPV = 84%: overall EIS accuracy = 79%. Pretest cancer probability of 51% (110 of 216) increased to 76% (96 of 127) post-EIS, and preoperative use of EIS would result in a significant reduction (71%, 75 of 106) in number of operations performed for benign nodules. EIS performance was similar for 109 patients with indeterminate FNA: Sn = 83%, Sp = 67%, PPV = 61%, NPV = 87%, accuracy = 73%. Pretest probability of cancer increased from 39% (42 of 109) to 61% (35 of 57) post-EIS. The use of EIS would result in a significant reduction (67%, 45 of 67) in the number of purely diagnostic thyroidectomy for indeterminate FNA. CONCLUSION: EIS shows promise in differentiating thyroid nodules. Further EIS hardware and software optimization is warranted to improve upon the already favorable negative predictive value in indeterminate thyroid nodules.