The properties of defects on the (100) MoS2 surface have been investigated by the perturbed cluster method. The perturbed cluster method provides an accurate description of the local defect properties while taking into account the interaction between the defect and the surrounding crystal. The surface energies, including correlation correction, of different defect structures of various sizes on the (100) MoS2 surface are reported and compared with the energy of a reference surface cluster. The results, in conjunction with calculations of the electronic properties and electrostatic potential of the different defect sites, show that the chemistry of the defects differs from that of the perfect (100) “as-cleaved” surface. The enhanced reactivity of the defects is ascribed to the anisotropy in the electrostatic potential. The presence of “nodes” in the surface electrostatic potential suggests that the adsorption of small polarizable molecules will preferentially take place in the vicinity of these defects.