A digital subtraction radiography (DSR) method was developed to assess changes of bony erosions in the hands of patients with rheumatoid arthritis (RA). The method initially was validated in vitro using simulated lesions in cadaver hands. The sensitivity, specificity and accuracy in detecting simulated lesions were 84.6, 100, and 92.3%, respectively. This technique was then pilot tested clinically using 17 patients with RA and 5 controls with no arthritis. All subjects received the nonsteroidal antiinflammatory drug, flurbiprofen, during the 6-month study period. No progressive changes in bone were observed in the control group; however, 18% of the target joints studied in the group with RA showed significant erosive changes (positive or negative) which correlated with the clinical assessment. The results indicate that DSR may be useful in detecting small changes in erosions on hand/wrist radiographs of patients with RA.