The stability constant (K), standard free energy (DeltaGdegrees), enthalpy (DeltaHdegrees), and entropy changes (TDeltaSdegrees) for the complexation of native alpha- and beta-cyclodextrins (CDs) and 6-amino-6-deoxy-beta-CD with more than 30 neutral, positively, and negatively charged guests, including seven fully or partially deuterated guests, have been determined in phosphate buffer solutions (pH/pD 6.9) of hydrogen oxide (H2O) or deuterium oxide (D2O) at 298.15 K by titration microcalorimetry. Upon complexation with these native and modified CDs, both nondeuterated and deuterated guests examined consistently exhibited higher affinities (by 5-20%) in D2O than in H2O. The quantitative affinity enhancement in D2O versus H2O directly correlates with the size and strength of the hydration shell around the charged/hydrophilic group of the guest. For that reason, negatively/positively charged guests, possessing a relatively large and strong hydration shell, afford smaller K-H2O/K-D2O ratios than those for neutral guests with a smaller and weaker hydration shell. Deuterated guests showed lower affinities (by 5-15%) than the relevant nondeuterated guests in both H2O and D2O, which is most likely ascribed to the lower ability of the C-D bond to produce induced dipoles and thus the reduced intracavity van der Waals interactions. The excellent enthalpy-entropy correlation obtained can be taken as evidence for the very limited conformational changes upon transfer of CD complexes from H2O to D2O.