Background: In preparation for 131 I ablation, temporary withdrawal of thyroid hormone is commonly used in patients with thyroid cancer after total thyroidectomy. The current study aimed to investigate brain glucose metabolism and its relationships with mood or cognitive function in these patients using F-18-fluoro-2-deoxyglucose positron emission tomography (F-18-FDG-PET). Method: A total of 40 consecutive adult patients with thyroid carcinoma who had undergone total thyroidectomy were recruited for this cross-sectional study. At the time of assessment, 20 patients were hypothyroid after two weeks of thyroid hormone withdrawal, while 20 received thyroid hormone replacement therapy and were euthyroid. All participants underwent brain F-18-FDG-PET scans and completed mood questionnaires and cognitive tests. Multivariate spatial covariance analysis and univariate voxel-wise analysis were applied for the image data. Results: The hypothyroid patients were more anxious and depressed than the euthyroid participants. The multivariate covariance analysis showed increases in glucose metabolism primarily in the bilateral insula and surrounding areas and concomitant decreases in the parieto-occipital regions in the hypothyroid group. The level of thyrotropin was positively associated with the individual expression of the covariance pattern. The decreased F-18-FDG uptake in the right cuneus cluster from the univariate analysis was correlated with the increased thyrotropin level and greater depressive symptoms in the hypothyroid group. Conclusions: These results suggest that temporary hypothyroidism, even for a short period, may induce impairment in glucose metabolism and related affective symptoms.