Objective: The aim of this study was to assess the performance and feasibility of ultra-high-frequency ultrasound (UHF-US) in clinical practice for measuring skin thickness in patients with systemic sclerosis (SSc) compared to age- and sex-matched controls. Materials and Methods: A total of 14 patients with SSc and 14 healthy controls (HCs) were enrolled in the study. All subjects underwent US evaluation of the epidermis, dermis and cutis by three experts in the 17 sites of the modified Rodnan skin score (mRSS). All the sonographers were blinded to the mRSS, which was assessed by an experienced rheumatologist who was not involved in, and blinded to, the US assessment. Results: In comparison to HCs, dermal thickness was significantly higher in patients at six sites: the right (p < 0.001) and left (p = 0.001) finger; right (p = 0.027) and left (p = 0.048) hand; left foot (p = 0.010) and face (p < 0.001). The epidermal layer did not differ significantly. At all mRSS sites except for the chest, there were moderate to strong positive correlations between US-assessed dermal thickness and local mRSS. The interobserver reliability for all sites of the mRSS, with the exception of the face, was good to excellent (with an intraclass correlation coefficient [ICC] ranging from 0.724 to 0.939). Conclusions: These data support the use of UHF-US as an objective and reliable tool for the assessment of skin involvement in patients with SSc. Considering its feasibility in clinical practice, we suggest that US assessment of skin in patients with SSc should be restricted to the dermal layer of the fingers and hands, since they are the sites that skin fibrosis typically starts from.