We have performed ab initio self-consistent field (SCF) and configuration interaction (CI) calculations on the active site of the aspartic proteinases pepsin and endothiapepsin. The active site, which carries a formal negative charge to effect hydrolysis, was modeled as a formic acid/formate anion moiety and a water molecule, and the nearest hydrogen bonding residues (Gly34, Ser35, Gly217, and Thr218, with respect to the residue numbering in endothiapepsin) were modeled as formamide and methanol molecules. Four possible binding modes for the active-site water molecule were considered. In contrast to previous theoretical studies, we predict that the most stable form has the water molecule forming a bifurcated hydrogen bond to the inner oxygens of Asp32 and -215, with Asp32 being ionized. The calculations suggest that the water molecule prefers to bind across the shortest OD32 ... OD215 diagonal of the active-site carboxyl groups and therefore the binding mode of the water molecule for all the native aspartic proteinases can be readily predicted by measuring these distances.