RT (RT)-PCR for thyroglobulin (Tg) and TSH receptor (TSHR) mRNA has been used to detect circulating thyroid cancer cells. Little is known, however, regarding the preoperative sensitivity of this test to detect cancer. Seventy-two patients with thyroid disease (36 with malignancy and 36 with benign disease) were evaluated preoperatively. TSHR and Tg mRNA transcripts were detected by RT-PCR assays, previously determined to be specific for cancer cells. There was 100% concordance between TSHR receptor and Tg mRNA RT-PCR results. Of 36 cancer patients, 11 had recurrent disease and all were positive by RT-PCR. Among 25 patients with no prior thyroid surgery 18 tested positive preoperatively (sensitivity 72%). Seven of 36 patients with benign disease tested positive (specificity 80%). The overall preoperative diagnostic accuracy was 77%. Forty-six of 61 patients with no prior thyroid surgery had preoperative fine needle aspiration (FNA) biopsy performed. FNA was diagnostic in 28 (61%) of patients. Preoperative cytology was adequate but not diagnostic in 18 (39%) patients. RT-PCR correctly classified 14 of these 18 patients with indeterminate FNA and detected 3/4 cancer patients as positive (75% sensitive) and was negative in 11/14 patients (78% specific) with benign disease. The combined diagnostic performance characteristics for RT-PCR and FNA cytology were sensitivity=95%, specificity=83% diagnostic accuracy=89% with positive and negative predictive values of 84% and 95% respectively. Our results suggest that the molecular detection of circulating thyroid cancer cells by RT-PCR for TSHR/Tg mRNA complements FNA cytology in the preoperative differentiation of benign from malignant thyroid disease and that their combined use may save unnecessary surgeries.