We present an analysis of the water molecules immobilized at the protein–protein interfaces of 115 homodimeric proteins and 46 protein–protein complexes, and compare them with 173 large crystal packing interfaces representing nonspecific interactions. With an average of 15 waters per 1000 Å2 of interface area, the crystal packing interfaces are more hydrated than the specific interfaces of homodimers and complexes, which have 10–11 waters per 1000 Å2, reflecting the more hydrophilic composition of crystal packing interfaces. Very different patterns of hydration are observed: Water molecules may form a ring around interfaces that remain “dry,” or they may permeate “wet” interfaces. A majority of the specific interfaces are dry and most of the crystal packing interfaces are wet, but counterexamples exist in both categories. Water molecules at interfaces form hydrogen bonds with protein groups, with a preference for the main-chain carbonyl and the charged side-chains of Glu, Asp, and Arg. These interactions are essentially the same in specific and nonspecific interfaces, and very similar to those observed elsewhere on the protein surface. Water-mediated polar interactions are as abundant at the interfaces as direct protein–protein hydrogen bonds, and they may contribute to the stability of the assembly. Proteins 2005. © 2005 Wiley-Liss, Inc.