Objectives. The purpose of this study was to evaluate the lossy Joint Photographic Experts Group compression for endodontic pretreatment digital radiographs. Study design. Fifty clinical charge-coupled device-based, digital radiographs depicting periapical areas were selected. Each image was compressed at 2, 4, 8, 16, 32, 48, and 64 compression ratios. One root per image was marked for examination. Images were randomized and viewed by four clinical observers under standardized viewing conditions. Each observer read the image set three times, with at least two weeks between each reading. Three pre-selected sites per image (mesial, distal, apical) were scored on a five-scale score confidence scale. A panel of three examiners scored the uncompressed images, with a consensus score for each site. The consensus score was used as the baseline for assessing the impact of lossy compression on the diagnostic values of images. The mean absolute error between consensus and observer scores was computed for each observer, site, and reading session. Results. Balanced one-way analysis of variance for all observers indicated that for compression ratios 48 and 64, there was significant difference between mean absolute error of uncompressed and compressed images (P < .05). After converting the five-scale score to two-level diagnostic values, the diagnostic accuracy was strongly correlated (R-2 = 0.91) with the compression ratio. Conclusion. The results of this study suggest that high compression ratios can have a severe impact on the diagnostic quality of the digital radiographs for detection of periapical lesions.