The activity of core-shell nanoparticles (NCs) in electrooxidation of methanol (MOR) was found to be dependent on the crystalline structure of the core and the lattice strain at the core-shell interface. Ru-core and Pt-shell NCs delivered 6.1-fold peak MOR current density at -135 mV than Pt NCs, while the Co-core and Pt-shell NCs showed a 1.4-fold peak MOR current density at 280 mV. The current density is improved by the compressive lattice strain of the surface that is caused by the lattice mismatch between the Pt shell and the Ru core. For Co-core NCs, the enhancement results from the ligand effect at surface Pt sites. In addition, the Ru-core NCs maintained a steady current density of 0.11 mA cm -2 at 500 mV in a half-cell system for 2 h, which is 100-fold higher than that of Pt NCs and Co-core NCs. These results provide mechanistic information for the development of fuel cell catalysts along with reduced Pt utilization and programmable electrochemical performance.