BACKGROUND: Patients with differentiated thyroid cancer (DTC) usually have a good prognosis. Traditionally, treatment success in patients with cancer has been evaluated by survival time. Recently, it has been observed that the diagnosis and treatment of cancer also have a strong effect on the quality of life (QOL) of these patients. OBJECTIVE: To assess the QOL of patients with DTC and its potential clinical predictors. DESIGN: Cross-sectional analysis. SETTING: A tertiary cancer institution. PATIENTS: One hundred fifty-four patients submitted to thyroidectomy (1997-2006) were evaluated using the University of Washington Quality of Life questionnaire. MAIN OUTCOME MEASURES: Descriptive analysis of the results was done, as bivariate and multivariate analyses to compare each independent variable with each of 13 QOL domains. RESULTS: Patients 45 years or younger had better recreation scores than did patients older than 45 years (P = .04). Thirty-eight patients were submitted to neck dissection. Patients submitted to modified radical neck dissection reported worse chewing and shoulder scores than did patients submitted to selective paratracheal lymph node dissection only and those without neck dissection (P = .003 and P = .004, respectively). Patients who received more than 150 mCi of radioactive iodine therapy (RIT) reported significantly worse pain, swallowing, chewing, speech, taste, anxiety, and composite scores. Comorbidities showed significant effect on recreation, activity, speech, saliva, and composite scores (P = .02, P = .046, P = .02, P = .01, and P = .008, respectively). In multivariate analysis, RIT is the only variable associated with a worse composite score (P = .003). CONCLUSION: Although QOL after treatment of thyroid cancer can be considered good for most patients, those submitted to RIT at doses higher than 150 mCi are at risk for poor QOL and, therefore, may need more intensive follow-up and treatment.