Homogeneous Charge Compression Ignition (HCCI) combustion technology has demonstrated a profound potential to decrease both emissions and fuel consumption. In this way, the significance of the 2-stroke HCCI engine has been underestimated as it can provide more power stroke in comparison to a 4-stroke engine. Moreover, the mass of trapped residual gases is much larger in a 2-stroke engine, causing higher initial charge temperatures, which leads to easier auto-ignition. For controlling 2-stroke HCCI engines, it is vital to find optimized simulation approaches of HCCI combustion with a focus on ignition timing. In this study, a Computational Fluid Dynamic (CFD) model for a 2-stroke gasoline engine was developed coupled to a semi-detailed chemical mechanism of iso-octane to investigate the simulation capability of the considered chemical mechanism and the effects of different simulation parameters such as the turbulence model, grid density and time step size. The validation of numerical results was carried using an experimental study on the 2-stroke engine that was modified to operate in HCCI mode. Results confirm that the considered iso-octane chemical mechanism is able to predict the ignition timing of HCCI combustion in the 2-stroke gasoline engine but special care has to be taken to the numerical setting like grid size, time step size and turbulence model. Furthermore, the k-ε RNG model is the best turbulence model for simulation of this case study coupled to the time step size of 0.25 crank angle degree and the average cell size of 1.35 mm.