Silica-reinforced natural rubber (NR) tire tread compounds with epoxidized natural rubber (ENR) as a compatibilizer are investigated. The ENRs consisting of 10, 38 and 51 mole% epoxide are used in a range of 2.5–15.0 parts per hundred parts of rubber (phr). The addition of ENRs, especially ENR-38 and ENR-51, decreases the Mooney viscosity, Payne effect, flocculation rate constant and filler networking factor, which implies an improvement of silica dispersion in the compounds. Chemically bound rubber contents and interaction parameters of the compounds also increase with higher epoxide-contents of the ENRs, indicating more interactions and/or reaction between the epoxide-groups of the ENR and silanol groups on the silica surface. Tensile strength of the vulcanizates is improved with increasing mole% epoxide, and the optimum value is observed at 7.5 phr of ENR-51. The overall results show that silica-reinforced NR can be substantially improved by adding ENR as a compatibilizer, when compared to a compound without ENR, but somewhat less than with using a silane coupling agent.