Reactivity Controlled Compression Ignition (RCCI) has been shown to be an attractive concept to achieve clean and high efficiency combustion. RCCI can be realized by applying two fuels with different reactivities, e.g., diesel and gasoline. This motivates the idea of using a single low reactivity fuel and direct injection (DI) of the same fuel blended with a small amount of cetane improver to achieve RCCI combustion. In the current study, numerical investigation was conducted to simulate RCCI and HCCI combustion and emissions with various fuels, including gasoline/diesel, iso-butanol/diesel and iso-butanol/iso-butanol+di-tert-butyl peroxide (DTBP) cetane improver. A reduced Primary Reference Fuel (PRF)-iso-butanol-DTBP mechanism was formulated and coupled with the KIVA computational fluid dynamic (CFD) code to predict the combustion and emissions of these fuels under different operating conditions in a heavy duty diesel engine. The results show that RCCI combustion is achievable by applying a single low reactivity fuel combined with small amount of DTBP cetane improver over wide operating conditions, and that the performance of the iso-butanol-DTBP fuel is comparable to that of gasoline-diesel and iso-butanol-diesel fuels. However, due to the low reactivity of iso-butanol, a relatively high amount of DTBP is needed to enhance the reactivity of the DI iso-butanol+DTBP mixture. The simulations were extended to also model homogeneous charge compression ignition (HCCI) combustion under similar operating conditions with the various fuels. Comparisons between HCCI and RCCI show that although comparable performance can be obtained with HCCI under low to medium load conditions, RCCI shows advantages under higher load conditions.