Progression to overt hypothyroidism and the associated adverse effects on lipid metabolism and the cardiovascular system are major concerns for patients diagnosed with subclinical hypothyroidism (SCH). No consensus regarding the clinical parameters associated with prognosis for this mild thyroid dysfunction has yet been established, although elevation of serum anti-thyroid peroxidase antibody (TPOAb) and decreased or heterogeneous echogenicity (diffuse thyroid disease, DT) on ultrasonography (US) are commonly observed. We investigated the value of ultrasonographic examination compared to the measurement of serum TPOAb and anti-thyroglobulin antibody (TgAb) for the evaluation of levothyroxine treatment on SCH. We analyzed 204 SCH patients who initially underwent thyroid ultrasonography and were given a low dose of levothyroxine for a mean of 6.94 months. Outcome was determined by the normalization or sustained elevation of serum TSH, and evaluated according to the presence of DT on subsequent US and serum TPOAb or TgAb. Sustained TSH elevation after levothyroxine replacement was more frequent in patients who initially showed DT on US, regardless of thyroid autoantibody level. Ultrasonographic morphology had a higher negative predictive value (81.8%) compared with the absence of TPOAb (73.9%) or TgAb (73.7%) and a similar positive predictive value (48.9%) to that of thyroid autoantibodies (46.8% for TPOAb and 50.0% for TgAb) in the outcome prediction of SCH. Thyroid US may provide valuable information on the course of SCH, and DT pattern can serve as a prognostic factor when combined with other known parameters.