Water is known to play an important role in the recognition and stabilization of the interaction between a ligand and its site. This has important implications for drug design. Analyses of 19 high-resolution crystal structures of protein-ligand complexes reveal the multiple hydrogen-bonding feature of water molecules mediating protein-ligand interactions. Most of the water molecules (nearly 80%) involved in bridging the protein and the ligand can make three or more hydrogen bonds when distance and bond angles are used as criteria to define hydrogen-bonding interactions. Isotropic B-factors have been used to take into account the mobility of water molecules. The water molecules at binding sites bridge the protein and ligand, and interact with other water molecules to form a complex network of interconnecting hydrogen bonds. Some water molecules at the site do not directly bridge between the protein and the ligand, but may contribute indirectly to the stability of the complex by holding bridging water molecules in the right position through a network of hydrogen bonds. These water networks are probably crucial for the stability of the protein-ligand complex and are important for any site-directed drug design strategies.