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Quantitative accuracy of single photon emission computed tomography (SPECT) images is highly dependent on the photon scatter model used for image reconstruction. Monte Carlo simulation (MCS) is the most general method for detailed modeling of scatter, but to date, fully three-dimensional (3-D) MCS-based statistical SPECT reconstruction approaches have not been realized, due to prohibitively long computation times and excessive computer memory requirements. MCS-based reconstruction has previously been restricted to two-dimensional approaches that are vastly inferior to fully 3-D reconstruction. Instead of MCS, scatter calculations based on simplified but less accurate models are sometimes incorporated in fully 3-D SPECT reconstruction algorithms. We developed a computationally efficient fully 3-D MCS-based reconstruction architecture by combining the following methods: 1) a dual matrix ordered subset (DM-OS) reconstruction algorithm to accelerate the reconstruction and avoid massive transition matrix precalculation and storage; 2) a stochastic photon transport calculation in MCS is combined with an analytic detector modeling step to reduce noise in the Monte Carlo (MC)-based reprojection after only a small number of photon histories have been tracked; and 3) the number of photon histories simulated is reduced by an order of magnitude in early iterations, or photon histories calculated in an early iteration are reused. For a 64×64×64 image array, the reconstruction time required for ten DM-OS iterations is approximately 30 min on a dual processor (AMD 1.4 GHz) PC, in which case the stochastic nature of MCS modeling is found to have a negligible effect on noise in reconstructions. Since MCS can calculate photon transport for any clinically used photon energy and patient attenuation distribution, the proposed methodology is expected to be useful for obtaining highly accurate quantitative SPECT images within clinically acceptable computation times.