Systemic sclerosis (scleroderma) is characterized by initial thickening of the skin because of the accumulation of collagen within the dermis followed by progression of fibrosis to internal organs. Although ultrasound assessment of dermal thickening in scleroderma patients is well documented, whether this technique can accurately detect skin thickening in mice under similar disease conditions is not known. Unlike traditional histologic assessments performed for disease models, ultrasound does not require sacrifice of the animal, and assessments of the same individual mice can be made over time. For these reasons, we examined the feasibility of ultrasound imaging to detect changes in skin thickness in a mouse model of graft-vs.-host-induced scleroderma (GVH-scleroderma). These studies determined ultrasound measurements to be highly consistent, both between multiple measurements of the same mouse as well as within a group of normal mice (coefficient of variation <8%). Ultrasound analysis of skin thickening in a GVH-scleroderma model showed similar sensitivity to histologic measurements because changes in skin thickness were detected by both methods at similar time points and to similar degrees. Direct comparisons between histologic and ultrasound measurements in the same animals over the course of disease also demonstrated significant correlations. Thus, these studies demonstrate that ultrasound can accurately detect skin thickening in a mouse model of scleroderma.