Single Photon Emission Computed Tomography (SPECT) suffers limited efficiency due to the need for collimators. Collimator properties largely decide the data statistics and image quality. Various materials and configurations of collimators have been investigated in many years. The main thrust of our study is to evaluate the design of pixel-geometry-matching collimators to investigate their potential performances using Geant4 Monte Carlo simulations. Here, a pixel-geometry-matching collimator is defined as a collimator which is divided into the same number of pixels as the detector’s and the center of each pixel in the collimator is a one-to-one correspondence to that in the detector. The detector is made of Cadmium Zinc Telluride (CZT), which is one of the most promising materials for applications to detect hard X-rays and γ-rays due to its ability to obtain good energy resolution and high light output at room temperature. For our current project, we have designed a large-area, CZT-based gamma camera (20.192 cm×20.192 cm) with a small pixel pitch (1.60 mm). The detector is pixelated and hence the intrinsic resolution can be as small as the size of the pixel. Materials of collimator, collimator hole geometry, detection efficiency, and spatial resolution of the CZT detector combined with the pixel-matching collimator were calculated and analyzed under different conditions. From the simulation studies, we found that such a camera using rectangular holes has promising imaging characteristics in terms of spatial resolution, detection efficiency, and energy resolution.