Recent advances have been made in a new class of CCD-based, single-photon-counting gamma-ray detectors which offer sub-100 μm intrinsic resolutions. 1-7 These detectors show great promise in small-animal SPECT and molecular imaging and exist in a variety of configurations. Typically, a columnar CsI(Tl) scintillator or a radiography screen (Gd 2O 2S:Tb) is imaged onto the CCD. Gamma-ray interactions are seen as clusters of signal spread over multiple pixels. When the detector is operated in a charge-integration mode, signal spread across pixels results in spatial-resolution degradation. However, if the detector is operated in photon-counting mode, the gamma-ray interaction position can be estimated using either Anger (centroid) estimation or maximum-likelihood position estimation resulting in a substantial improvement in spatial resolution. 2 Due to the low-light-level nature of the scintillation process, CCD-based gamma cameras implement an amplification stage in the CCD via electron multiplying (EMCCDs) 8-10 or via an image intensifier prior to the optical path. 1 We have applied ideas and techniques from previous systems to our high-resolution LumiSPECT detector. 11,12 LumiSPECT is a dual-modality optical/SPECT small-animal imaging system which was originally designed to operate in charge-integration mode. It employs a cryogenically cooled, high-quantum-efficiency, back-illuminated large-format CCD and operates in single-photon-counting mode without any intermediate amplification process. Operating in photon-counting mode, the detector has an intrinsic spatial resolution of 64 μm compared to 134 μm in integrating mode.