MoSi2 is a potential high temperature structural materials and shows excellent oxidation resistance at high temperatures. To explore its oxidation behaviour and mechanism, MoSi2 single crystals were prepared and investigated in the present work. The experimental results showed that different from its polycrystalline, MoSi2 single crystal showed good oxidation resistance at both 773 and 1473K. Near parabolic law of oxidation kinetics was followed for all the investigated surfaces of MoSi2 single crystal. The close-packed (110) surface of MoSi2 single crystal showed the best oxidation resistance at both temperatures. After exposure at 773K, the molybdenum oxide formed on the (110) surface of MoSi2 single crystal was found to be Mo4O11 instead of MoO3 formed on the other surfaces. Morphology observation showed a columnar growth of Mo4O11 on the (110) surface. No difference was found on the oxide formed for different surfaces of MoSi2 single crystal at 1473K.