Solvation of pharmaceutical drugs has an important effect on their structure and function. Analysis of infrared photodissociation spectra of amantadineH⁺(H₂O)_n=1–4 clusters in the sensitive OH, NH, and CH stretch range by quantum chemical calculations (B3LYP-D3/cc-pVTZ) provides a first impression of the interaction of this pharmaceutically active cation with water at the molecular level. The size-dependent frequency shifts reveal detailed information about the acidity of the protons of the NH₃⁺ group of N-protonated amantadineH⁺ (AmaH⁺) and the strength of the NH⋯O and OH⋯O hydrogen bonds (H-bonds) of the hydration network. The preferred cluster growth begins with sequential hydration of the NH₃⁺ group by NH⋯O ionic H-bonds (n = 1–3), followed by the extension of the solvent network through OH⋯O H-bonds. However, smaller populations of cluster isomers with an H-bonded solvent network and free N–H bonds are already observed for n ≥ 2, indicating the subtle competition between noncooperative ion hydration and cooperative H-bonding. Interestingly, cyclic water ring structures are identified for n ≥ 3, each with two NH⋯O and two OH⋯O H-bonds. Despite the increasing destabilization of the N–H proton donor bonds upon gradual hydration, no proton transfer to the (H₂O)_n solvent cluster is observed up to n = 4. In addition to ammonium cluster ions, a small population of microhydrated iminium isomers is also detected, which is substantially lower for the hydrophilic H₂O than for the hydrophobic Ar environment.