CONTEXT: TSH is a known thyroid growth factor, but the pathogenic role of TSH in thyroid oncogenesis is unclear. OBJECTIVE: The aim was to examine the relationship between preoperative TSH and differentiated thyroid cancer (DTC). DESIGN: The design was a retrospective cohort. SETTING, PARTICIPANTS: Between May 1994 and January 2007, 1198 patients underwent thyroid surgery at a single hospital. Data from the 843 patients with preoperative serum TSH concentration were recorded. MAIN OUTCOME MEASURES: Serum TSH concentration was measured with a sensitive assay. Diagnoses of DTC vs. benign thyroid disease were based on surgical pathology reports. RESULTS: Twenty-nine percent of patients (241 of 843) had DTC on final pathology. On both univariate and multivariable analyses, risk of malignancy correlated with higher TSH level (P=0.007). The likelihood of malignancy was 16% (nine of 55) when TSH was less than 0.06 mIU/liter vs. 52% (15 of 29) when 5.00 mIU/liter or greater (P=0.001). When TSH was between 0.40 and 1.39 mIU/liter, the likelihood of malignancy was 25% (85 of 347) vs. 35% (109 of 308) when TSH was between 1.40 and 4.99 mIU/liter (P=0.002). The mean TSH was 4.9+/-1.5 mIU/liter in patients with stage III/IV disease vs. 2.1+/-0.2 mIU/liter in patients with stage I/II disease (P=0.002). CONCLUSIONS: The likelihood of thyroid cancer increases with higher serum TSH concentration. Even within normal TSH ranges, a TSH level above the population mean is associated with significantly greater likelihood of thyroid cancer than a TSH below the mean. Shown for the first time, higher TSH level is associated with advanced stage DTC.