The blending of ethanol with primary reference fuel (PRF) mixtures, comprising n-heptane and iso-octane, is known to exhibit non-linear octane response. However, the underlying chemistry and intermolecular interactions are poorly understood. Well-designed experiments and numerical simulations are required to understand these blending effects and the chemical kinetic phenomenon responsible for them. To this end, HCCI engine experiments were previously performed at four different conditions of intake temperature and engine speed for various PRF/ethanol mixtures. Transfer functions were developed in the HCCI engine to relate PRF mixture composition to autoignition tendency at various compression ratios. The HCCI blending octane number (BON) was determined for mixtures of 2-15 vol% ethanol with each of PRF70 and PRF84. In the present work, the experimental conditions were utilized to perform zero-dimensional HCCI engine simulations with detailed chemical kinetics for ethanol/PRF blends. The simulations utilized the actual engine geometry and estimated intake valve closure conditions to replicate the experimentally measured start of combustion (SOC) for various PRF mixtures. The simulated compression ratio required for SOC of various PRF mixtures was used to generate transfer functions at each of the four HCCI operating modes. Similar simulations for each of the ethanol/PRF blends determined the compression ratio corresponding to SOC, and were combined with the respective transfer functions to yield HCCI BON. The simulated HCCI BON were shown to reproduce the experimentally observed trends, specifically on the effectiveness of ethanol as an ignition inhibitor at various concentrations. Detailed analysis of simulated heat release profiles and the evolution of important radical intermediates (e.g., OH and HO2) were used to show the effect of ethanol blending of controlling reactivity. A strong coupling between ethanol’s low temperature oxidation reactions and those of n-heptane and iso-octane are shown to be responsible for the observed blending effects of ethanol/PRF mixtures.