We have developed a refined computer-based method to detect joint space narrowing (JSN) progression with the joint space narrowing progression index (JSNPI) by superimposing sequential hand radiographs. The purpose of this study is to assess the validity of a computer-based method using images obtained from multiple institutions in rheumatoid arthritis (RA) patients. Sequential hand radiographs of 42 patients (37 females and 5 males) with RA from two institutions were analyzed by a computer-based method and visual scoring systems as a standard of reference. The JSNPI above the smallest detectable difference (SDD) defined JSN progression on the joint level. The sensitivity and specificity of the computer-based method for JSN progression was calculated using the SDD and a receiver operating characteristic (ROC) curve. Out of 314 metacarpophalangeal joints, 34 joints progressed based on the SDD, while 11 joints widened. Twenty-one joints progressed in the computer-based method, 11 joints in the scoring systems, and 13 joints in both methods. Based on the SDD, we found lower sensitivity and higher specificity with 54.2 and 92.8%, respectively. At the most discriminant cutoff point according to the ROC curve, the sensitivity and specificity was 70.8 and 81.7%, respectively. The proposed computer-based method provides quantitative measurement of JSN progression using sequential hand radiographs and may be a useful tool in follow-up assessment of joint damage in RA patients.