Single photon emission computed tomography (SPECT) is at present one of the major techniques for non-invasive diagnostics in nuclear medicine. The clinical routine is mostly based on collimated cameras, originally proposed by Hal Anger. Due to the presence of mechanical collimation, detection efficiency and energy acceptance are limited and fixed by the system's geometrical features. In order to overcome these limitations, the application of Compton cameras for SPECT has been investigated for several years.In this study we compare a commercial SPECT-Anger device, the General Electric HealthCare Infinia system with a High Energy General Purpose (HEGP) collimator, and the Compton camera prototype under development by the French collaboration CLaRyS, through Monte Carlo simulations (GATE—GEANT4 Application for Tomographic Emission—version 7.1 and GEANT4 version 9.6, respectively). Given the possible introduction of new radio-emitters at higher energies intrinsically allowed by the Compton camera detection principle, the two detectors are exposed to point-like sources at increasing primary gamma energies, from actual isotopes already suggested for nuclear medicine applications. The Compton camera prototype is first characterized for SPECT application by studying the main parameters affecting its imaging performance: detector energy resolution and random coincidence rate. The two detector performances are then compared in terms of radial event distribution, detection efficiency and final image, obtained by gamma transmission analysis for the Anger system, and with an iterative List Mode-Maximum Likelihood Expectation Maximization (LM-MLEM) algorithm for the Compton reconstruction.The results show for the Compton camera a detection efficiency increased by a factor larger than an order of magnitude with respect to the Anger camera, associated with an enhanced spatial resolution for energies beyond 500 keV. We discuss the advantages of Compton camera application for SPECT if compared to present commercial Anger systems, with particular focus on dose delivered to the patient, examination time, and spatial uncertainties.