OBJECTIVE. This study was performed to determine the rates and causes of disagreements in interpretation between full-field digital mammography and film-screen mammography in a diagnostic setting. SUBJECTS AND METHODS. Patients undergoing diagnostic mammography were invited to participate in the digital mammography study. Three views, selected by the radiologist interpreting the film-screen mammography, were obtained in both film-screen mammography and digital mammography. Radiologists independently assigned a Breast Imaging Reporting and Data System (BI-RADS) category to the film-screen mammography and the digital mammography images. The BI-RADS categories were grouped into the general categories of agreement, partial agreement, or disagreement. A third and different radiologist reviewed all cases of disagreement, reached a decision as to management, and determined the primary cause of disagreement. RESULTS. Six radiologists reviewed digital mammography and film-screen mammography diagnostic images in a total of 1147 breasts in 692 patients. Agreement between digital mammography and final film-screen mammography assessment was present in 937 breasts (82%), partial agreement in 159 (14%), and disagreement in 51 (4%), for a kappa value of 0.29. The primary causes of disagreement were differences in management approach of the radiologists (52%), information derived from sonography or additional film-screen mammograms (34%), and technical differences between the two mammographic techniques (10%). CONCLUSION. Significant disagreement between film-screen mammography and digital mammography affecting follow-up management was present in only 4% of breasts. The most frequent cause of disagreement in interpretation was a difference in management approach between radiologists (interobserver variability). This source of variability was larger than that due to differences in lesion visibility between film-screen mammography and digital mammography.