Based on first-principle calculations, the effects of the intrinsic point defects, including single Se vacancy and single In vacancy, on the interaction of O-2 and H2O molecules with the InSe monolayer are theoretically studied. Both vacancies can significantly enhance the chemical activity of InSe toward the adsorbates. However, H2O molecules highly tend to be physisorbed on the InSe monolayers under ambient conditions, irrespective of the presence of the vacancies. Both the pristine InSe and that with the In vacancy are p-doped by H2O, while the InSe with the Se vacancy is n-doped by H2O. O-2 molecules with p-doping effects also highly tend to be physisorbed on the pristine InSe monolayer, while the presence of the vacancies significantly facilitates the O-2 dissociation. The O-2 dissociation process on the pristine InSe monolayer is endothermic by 1.24 eV and needs to overcome an energy barrier of 2.85 eV. However, In vacancies make the O-2 dissociation process on the InSe monolayer exothermic by 2.15 eV with an energy barrier of similar to 1.0 eV. Significantly, O-2 dissociation on the InSe monolayers with Se vacancies are highly exothermic by 4.57 eV with an energy barrier of only 0.17 eV. These results suggest that the defects with agglomerated vacancies, such as edges and grain boundaries, may play an important role in the oxidation and degradation of the 2D InSe under ambient conditions. Our theoretical results can help better understanding the doping and the oxidation of the 2D InSe semiconductor under ambient conditions. (C) 2017 Elsevier B.V. All rights reserved.