The aim of this work was twofold: (1) to examine whether, with standard automatic exposure control (AEC) settings that maintain pixel values in the detector constant, lesion detectability in clinical images decreases as a function of breast thickness and (2) to verify whether a new AEC setup can increase lesion detectability at larger breast thicknesses. Screening patient images, acquired on two identical digital mammography systems, were collected over a period of 2 yr. The images were divided into four thickness groups: T1 ≤ 29 mm, T2 = 30–49 mm, T3 = 50–69 mm, and T4 ≥ 70 mm, with each thickness group containing 130 randomly selected craniocaudal lesion-free images. One selected lesion (a microcalcification cluster or a mass) was simulated into each of the four images. Finally, all images were visualized using the ViewDEX software and scored by four radiologists performing a free search study. A statistical jackknife-alternative free-response receiver operating characteristic analysis was applied. For part 1, the alternative free-response receiver operating characteristic curves for the four readers were 0.80, 0.65, 0.55 and 0.56 in going from T1 to T4, indicating a decrease in detectability with increasing breast thickness. P-values and the 95% confidence interval showed no significant difference for the T3-T4 comparison (p = 0.78) while all the other differences were significant (p <0.05). Separate analysis of microcalcification clusters presented the same results while for mass detection, the only significant difference came when comparing T1 to the other thickness groups. Comparing the scores of part 1 and part 2, results for the T3 group acquired with the new AEC setup and T3 group at standard AEC doses were significantly different (p = 0.0004), indicating improved detection. For this group a subanalysis for microcalcification detection gave the same results while no significant difference was found for mass detection. These data using clinical images confirm results found in simple QA tests for many mammography systems that detectability falls as breast thickness increases. Results obtained with the AEC setup for constant detectability above 49 mm showed an increase in lesion detection with compressed breast thickness, bringing detectability of lesions to the same level.