Collisional dynamics of size- and translational-energy-selected protonated water clusters H+(H2O)(n) (n = 2-11) in single collisions with D2O were investigated using guided-ion beam tandem mass spectrometry. The dominant reaction channel for the collision involves the incorporation of D2O into H+(H2O)(n) at low collision energy, whereas at high collision energy, the dissociation of H+(H2O)(n) is predominant. The measured total reaction cross section of H+(H2O)(n) with D2O is found to depend strongly on the cluster size; the cross section drastically increases as the cluster size increases from n = 4 to 5, 6 to 7, and 8 to 9 and has local minima at n = 6 and 8 at collision energies of 0.05 and 0.10 eV, respectively. The size dependence of the total cross section is discussed herein in terms of a comparison with the collision cross section obtained from ab initio calculations.