Purpose:To optimize the cesium iodide (CsI:Tl) scintillator thickness in a complimentary metal‐oxide semiconductor (CMOS)‐based detector for use in dedicated cone‐beam breast CT.Methods:The imaging task considered was the detection of a microcalcification cluster comprising six 220µm diameter calcium carbonate spheres, arranged in the form of a regular pentagon with 2 mm spacing on its sides and a central calcification, similar to that in ACR‐recommended mammography accreditation phantom, at a mean glandular dose of 4.5 mGy. Generalized parallel‐cascades based linear systems analysis was used to determine Fourier‐domain image quality metrics in reconstructed object space, from which the detectability index inclusive of anatomical noise was determined for a non‐prewhitening numerical observer. For 300 projections over 2π, magnification‐associated focal‐spot blur, Monte Carlo derived x‐ray scatter, K‐fluorescent emission and reabsorption within CsI:Tl, CsI:Tl quantum efficiency and optical blur, fiberoptic plate transmission efficiency and blur, CMOS quantum efficiency, pixel aperture function and additive noise, and filtered back‐projection to isotropic 105µm voxel pitch with bilinear interpolation were modeled. Imaging geometry of a clinical prototype breast CT system, a 60 kV Cu/Al filtered x‐ray spectrum from 0.3 mm focal spot incident on a 14 cm diameter semi‐ellipsoidal breast were used to determine the detectability index for 300–600 µm thick (75µm increments) CsI:Tl. The CsI:Tl thickness that maximized the detectability index was considered optimal.Results:The limiting resolution (10% modulation transfer function, MTF) progressively decreased with increasing CsI:Tl thickness. The zero‐frequency detective quantum efficiency, DQE(0), in projection space increased with increasing CsI:Tl thickness. The maximum detectability index was achieved with 525µm thick CsI:Tl scintillator. Reduced MTF at mid‐to‐high frequencies for 600µm thick CsI:Tl lowered the detectability index than 525µm CsI:Tl.Conclusion:For the x‐ray spectrum and imaging conditions considered, a 525µm thick CsI:Tl scintillator integrated with the CMOS detector is optimal for detecting microcalcification cluster.Funding support: Supported in part by NIH R01 CA195512. The contents are solely the responsibility of the authors and do not reflect the official views of the NIH or the NCI. Disclosures: SV, GV and AK ‐ Research collaboration, Koning Corp., West Henrietta, NY.