The positron binding abilities of proline and its hydrated clusters were theoretically studied using multicomponent molecular orbital (MC_MO) calculations. Low-lying equilibrium structures of the neutral proline·(H2O) n ( n = 0-2) clusters were systematically explored with the aid of global reaction route mapping code. The positron binding energies were then calculated for the equilibrium structures. We found that the zwitterionic forms generally displayed high positron binding energies owing to their highly polar nature. We also found that nonzwitterionic forms can exhibit high positron binding energies if the addition of water significantly increases the total electric dipole moment. These results demonstrate that the most stable positron-bound proline·(H2O) n ( n = 1 and 2) structures are more stable than the most stable neutral structures, which implies that the attachment of a positron to a neutral hydrated proline cluster can induce structural changes if the positron-electron annihilation lifetime is sufficiently long relative to the time scale of nuclear motion. We also examined the influence of positron binding on the energy profiles of the proton transfer reactions from the nonzwitterionic form to the zwitterionic form.