The objective of the study is to evaluate multi-site quantitative ultrasound (QUS) in comparison to dual energy X-ray absorptiometry (DXA) considering the effects of body mass index (BMI) and disease activity on measurements in patients suffering from rheumatoid arthritis (RA). Sixty-eight patients underwent a cross-sectional analysis of bone mineral density measured by DXA (lumbar spine, total femur) and speed of sound estimated by QUS (phalanx III, distal radius). The short-term precision of QUS was investigated with regard to BMI of healthy individuals and with regard to the level of disease activity in patients suffering from RA. The patients with RA were divided into two BMI groups as well as into low and advanced disease activity groups. The short-term precision of QUS-SOS ranged from 0.90 to 2.55% (healthy controls) and from 0.64 to 1.89% (patients with RA). The association between DXA and QUS parameters were limited in the case of advanced disease activity and pronounced BMI. Low QUS-SOS was observed for advanced disease activity group (QUS-SOS phalanx: -2.5%; QUS-SOS distal radius: -2.1%) in comparison to low disease activity group, whereas only a slight change of DXA parameters was observed. DXA-BMD and QUS parameters revealed higher values with pronounced BMI. The system shows only a short-term precision with limitations in healthy controls with accentuated BMI, as well as in patients with active RA. The application of multi-site QUS seems to be restricted for patients with active inflammation based on soft tissue alteration in RA and for healthy individuals with pronounced body mass.