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We propose a design for a high-resolution SPECT system for in vivo 125I imaging in small animal using pixelated lithium-drifted silicon (Si(Li)) detectors. The detectors have high detection efficiency (>90%), good energy resolution (<15% FWHM), and good intrinsic spatial resolution (∼1 mm FWHM). The SPECT system has a dual head detector geometry with the distance between the detectors ranging 30-50 mm to allow for the shortest imaging distance between the mouse and the detectors. The detectors, each with an active area of 64 mm×40 mm (64×40 array of 1 mm2 pixels and a 6 mm thick Si(Li) detector), are mounted on a rotating gantry with an axial field-of-view of 64 mm. Using a high-resolution parallel-hole collimator, the expected spatial resolution is 1.6 mm FWHM at an imaging distance of 20 mm, and sensitivity is 6.7 cps/μCi. 125I is a readily available radioisotope with a long half-life of 59.4 days and it is commonly used to label biological compounds in molecular biology. Conventional gamma cameras are not optimized to detect the low emission energies (27 to 35 keV) of 125I. However, Si(Li) detector provides an ideal solution for detecting the low-energy emissions of 125I. In addition, a SPECT system based on Si(Li) detector can potentially be less expensive than other detector technology because of its ease of operation and the availability of many resources for processing silicon. This will increase the availability of small-animal SPECT systems in biomedical research, thereby providing an important tool to facilitate the research in mouse biology.