Full-field digital mammography (FFDM) with soft-copy reading is more complex than screen-film mammography (SFM) with hard-copy reading. The aim of this study was to compare inter- and intraobserver variability in SFM versus FFDM of paired mammograms from a breast cancer screening program. Six radiologists interpreted mammograms of 232 cases obtained with both techniques, including 46 cancers, 88 benign lesions, and 98 normals. Image interpretation included BI-RADS categories. A case consisted of standard two-view mammograms of one breast. Images were scored in two sessions separated by 5 weeks. Observer variability was substantial for SFM as well as for FFDM, but overall there was no significant difference between the observer variability at SFM and FFDM. Mean kappa values were lower, indicating less agreement, for microcalcifications compared with masses. The lower observer agreement for microcalcifications, and especially the low intraobserver concordance between the two imaging techniques for three readers, was noticeable. The level of observer agreement might be an indicator of radiologist performance and could confound studies designed to separate diagnostic differences between the two imaging techniques. The results of our study confirm the need for proper training for radiologists starting FFDM with soft-copy reading in breast cancer screening.