This study aimed to assess the diagnostic performance of computed tomography (CT) for differentiating diffuse thyroid disease (DTD) from normal thyroid parenchyma (NTP) using multicenter data. Between January 2016 and June 2016, 229 patients underwent preoperative neck CT and subsequent thyroid surgery at five participating institutions. The neck CT images of each patient were retrospectively reviewed and classified into the following four categories: no DTD, indeterminate, suspicious for DTD, and DTD. The results of the CT image evaluations were compared with the histopathological results to determine the diagnostic accuracy of CT at each institution. According to the histopathological results, there were NTP (n = 151), Hashimoto thyroiditis (n = 24), non-Hashimoto lymphocytic thyroiditis (n = 47), and diffuse hyperplasia (n = 7). The CT categories of the 229 patients were “no DTD” in 89 patients, “indeterminate” in 40 patients, “suspicious for DTD” in 42 patients, and “DTD” in 58 patients. The presence of two or more CT features of DTD, which was classified as “suspicious for DTD” by all radiologists, had the largest area under the receiver-operating characteristic curve (Az = 0.820; 95% confidence interval: 0.764, 0.868), with sensitivity of 85.9% and specificity of 78.2%. However, no statistical significance between readers’ experience and their diagnostic accuracy was found. In conclusion, evaluations of CT images are helpful for differentiating DTD from NTP.