Octane sensitivity (OS), as one of the fuel anti-knock quality indexes, is critical with respect to the effective design of next-generation spark ignition (SI) engines. This simulation study focuses on the effects of OS on knock behavior as a function of spark timing (ST) and compression ratio (CR) under boosted high load condition. Eight fuels with identical Research Octane Number (RON) and varying OS were selected to specify the relationship between OS and fuel-specific properties, including a primary reference fuel (PRF), Ethanol Reference Fuels (ERFs), Toluene Reference Fuels (TRFs). It was found that increasing OS to decrease end-gas reactivity is conditional. The end-gas reactivity becomes less sensitive to OS with advancing ST. Analysis for the relationship between OS and fuel-specific properties illustrate that fuel-specific variations beyond OS play an important role in knock tendency when increasing CR, where OS value is insufficient to describe the fuel anti-knock performance. ERF yields better knock resistance than the corresponding OS TRF at high CR conditions. The cause for this behavior is that the decrease in the autoignition temperature moves the end-gas of high OS fuel into a long-ignition-delay region. Comparable chemical and charge cooling effects are effective to retard auto-ignition more dramatically for ERFs.