Phospholipase A(2) is a calcium-dependent enzyme involved in inflammatory processes by releasing arachidonic acid from the sn-2 position of phosphatidyl-cholines. The catalyzed reaction is an ester hydrolysis that takes place in two proton transfer steps via an intermediate. Two mechanisms, which differ mainly in the rate-limiting step, have been proposed in the literature. The reaction has been calculated semiempirically (PM3) for a protein fragment containing the active site (156 atoms). To take long-range electrostatic interactions of the protein bulk with the active site into account, a classical-mechanical protein environment has been provided by a rigid point-charge array with associated van der Waals potentials. In this way a model system has been built that simulates the natural situation in an enzyme more realistically than a pure model of the active site. A comparison between the relative energy paths obtained by calculating the reaction in the isolated active site and within the classical mechanical environment shows that the long-range interactions have a strong influence on the mechanism. While the calculations of the smaller system indicate that the first reaction step, the formation of the intermediate, is rate-limiting, the calculations including the protein environment show that the decomposition of the intermediate is probably rate-limiting. The results clearly show that the protein environment cannot be disregarded during quantum-mechanical calculations of enzyme mechanisms.