The purpose of this study was to compare the thickness of the compressed breast between mediolateral oblique and craniocaudal mammograms and to relate these differences in thickness to image quality and radiation dose. These differences may partially explain why some subtle tumors are better visualized on the craniocaudal view. The study population consisted of 250 paired mediolateral oblique and craniocaudal mammograms obtained on one mammographic unit by seven certified mammography technologists during a 2-month period. Only women with breast implants, prior lumpectomy and radiotherapy, or chest wall deformity were excluded. The digital readout of compressed breast thickness and applied compression force was recorded. Mammographic positioning was assessed using standard criteria. Absorbed radiation dose at different thicknesses was measured with a BR-12 breast phantom. Image quality differences for geometric unsharpness and contrast were calculated for the observed breast thickness differences between mediolateral oblique and craniocaudal mammograms. The mean thickness of the compressed breast on the craniocaudal view was less than the mean thickness on the mediolateral oblique view (4.4 versus 4.8 cm, p < .0001) despite the greater force used to compress the breast for mediolateral oblique than for craniocaudal views (93 versus 86 newtons, p < .0001). The breast thickness on the mediolateral oblique view exceeded that on the craniocaudal view in 98 (84%) of 117 pairs that differed in thickness by 5 mm or more and 46 (94%) of 49 pairs that differed by 10 mm or more (p < .0001). Geometric unsharpness increased by 8% and 19% when a 4.4-cm-thick breast was compared to a 4.8- and 5.4-cm-thick breast, respectively. A 5% and 12% loss of contrast was noted when a 4.4-cm-thick breast was compared to a 4.8- and 5.4-cm-thick breast. Mean glandular radiation dose at 4.4, 4.8, and 5.4 cm was 1.40, 1.70, and 2.33 mGy, respectively. The compressed breast is 8% thicker on mediolateral oblique than on craniocaudal mammograms, a small but statistically significant difference. This difference results in a small loss of spatial and contrast resolution on the mediolateral oblique views and an increase in radiation dose. These image quality differences may partially explain why some subtle carcinomas are better visualized on the craniocaudal view.