The present study deals with a comparative evaluation of a single-zone (SZ) thermodynamic model and a 3D computational fluid dynamics (CFD) model for heat release calculation in internal combustion engines. The first law, SZ, model is based on the first law of thermodynamics. This model is characterized by a very simplified modeling of the combustion phenomenon allowing for a great simplicity in the mathematical formulation and very low computational time. The CFD 3D models, instead, are able to solve the chemistry of the combustion process, the interaction between turbulence and flame propagation, the heat exchange with walls and the dissociation and re-association of chemical species. They provide a high spatial resolution of the combustion chamber as well. Nevertheless, the computation requirements of CFD models are enormously larger than the SZ techniques. However, the SZ model needs accurate experimental in-cylinder pressure data for initializing the heat release calculation. Therefore, the main objective of an SZ model is to evaluate the heat release, which is very difficult to measure in experiments, starting from the knowledge of the in-cylinder pressure data. Nevertheless, the great simplicity of the SZ numerical formulation has a margin of uncertainty which cannot be known a priori. The objective of this paper was, therefore, to evaluate the level of accuracy and reliability of the SZ model comparing the results with those obtained with a CFD 3D model. The CFD model was developed and validated using cooperative fuel research (CFR) engine experimental in-cylinder pressure data. The CFR engine was fueled with 2,2,4-trimethylpentane, at a rotational speed of 600 r/min, an equivalence ratio equal to 1 and a volumetric compression ratio of 5.8. The analysis demonstrates that, considering the simplicity and speed of the SZ model, the heat release calculation is sufficiently accurate and thus can be used for a first investigation of the combustion process.