Differentiated thyroid carcinoma (DTC) generally has a favorable outcome. Thyroid disease, treatments, stress, and comorbidity can compromise health-related quality of life (QoL) and indirectly weigh upon the outcome. From 2004 to 2008, we evaluated QoL longitudinally in 128 DTC subjects. During scheduled examinations, subjects were asked to undergo a semi-structured psychiatric interview and five rated inventories. The same examination was conducted in 219 subjects after surgery for benign thyroid pathology. Low scores represent a better QoL. DTC and control subjects were similar in terms of age, male/female ratio, concomitant psychopharmacological treatments, and frequency of psychiatric diseases. In DTC subjects, Billewicz scale (BS) scores showed an increasing trend over time, especially among females. The ad hoc thyroid questionnaire (TQ) scores were similar in both groups and did not change over time, but at the end of the study ad hoc TQ and BS were significantly related. Ad hoc TQ scores were also related to age on entry to the study. In both male and female DTC subjects, Hamilton’s tests for anxiety (HAM-A), but not for depression (HAM-D), showed an improving trend. At the end of the study, HAM-A and HAM-D scores were comparable to those of the control group. HAM-A and HAM-D were both positively correlated with the stage of cancer and the time between diagnosis and treatment. Only HAM-D correlated with age on entry to the study. Kellner symptom questionnaire (KSQ) item scores were higher in DTC subjects than in controls. The change over time in the items including anxiety, somatization, depression, and hostility was significant. Somatization and hostility were more significantly reduced in DTC females than in DTC males. Hostility scores were significantly lower in DTC subjects than in controls at the end of the study. Somatization and depression were significantly related to staging on diagnosis and age on entry to the study. Our study confirms a wide variation of illness perception in DTC subjects, which is generally unrelated to the favorable clinical follow-up of the disease. Psychological evaluation during long-term follow-up improved QoL scores, which reached the same levels noted in subjects with a history of thyroid surgery for benign thyroid pathology. Our data indicate that special attention should be paid to QoL in older DTC subjects and those with more severe staging on diagnosis.