Objective: Considering the limited data available on the natural course of euthyroidism, this study was designed to evaluate the progression in time from euthyroidism to subclinical or overt hypo-or hyperthyroidism. Methods: This study was conducted within the framework of the Tehran Thyroid Cohort Study, in which 5783 individuals aged 40.4 +/- 0.2 years were followed for six years. The overall loss to follow-up rate was 8.3%. After applying exclusion criteria, data of 4204 euthyroid subjects remained for analysis of a six-year natural course analysis. Thyroid function tests, clinical characteristics, and metabolic characteristics were assessed at baseline and every three years. Results: The annual incidence rates [confidence intervals (CI)] of subclinical and overt hypothyroidism were 7.62 [CI 7.39-7.85) and 2.0 [CI 1.94-2.06] per 1000 persons, respectively. For thyroid hyperfunction, the annual incidence rates of subclinical and overt hyperthyroidism were 0.92 [0.90-0.95) and 0.68 [0.66-0.70) per 1000 persons, respectively. Euthyroid persistency was 93.24% during 6 years. Predictive factors for conversion to thyroid dysfunction were thyrotropin, free thyroxine and thyroid peroxidase antibody levels, sex, and smoking. Criteria for early diagnosis of hypothyroidism (i.e., sensitivity of 94% and specificity of 82%, p < 0.0001) were obtained based on baseline and three-year follow-ups of thyroid function tests and thyroid peroxidase antibody. Early diagnosis of hypothyroidism was significantly associated with impaired glucose tolerance (relative risk with 3.03 [CI 1.36-6.75]; p = 0.007), high cholesterol (relative risk 2.46 [CI 1.45-4.18]; p = 0.001), obesity (relative risk 2.92 [CI 1.64-5.2]; p < 0.001), and hypertension (relative risk 1.68 [CI 1.53-1.84]; p < 0.04). Conclusion: This study shows that after a six-year follow-up in an iodine sufficient area, 6.7% of euthyroid subjects were found to progress to thyroid dysfunction, in particular subclinical hypothyroidism.