We combined quantum mechanics/molecular mechanics calculations with molecular dynamics simulations to study the addition of O2 to the pentadienyl radical of arachidonic acid (AA) catalyzed by the Leu597Val and Leu597Ala mutants of rabbit 15-lipoxygenase (15-rLO). In the Leu597Val mutant, the addition of O2 to C15 of AA is the predominant path, although it reduces the C15/C11 product ratio by almost ten times with respect to the wildtype enzyme. The S stereochemistry is kept. Mutation to Ala causes just the opposite effect: regiospecificity favoring addition to C15 is somewhat sharper than that in the wildtype, but the stereochemistry is R. This is because the extra space created by the mutation to Ala is big enough for AA to move so that it can adopt an alternative binding mode, and this opens new feasible paths for the attack of O2. So, we showed that the Leu597Ala mutant of 15r-LO works as an aspirin-acetylated cyclooxygenase-2, which makes 15-(R)- hydroperoxyeicosatetraenoic acid. Mutant powers: Quantum mechanics/molecular mechanics are used to analyze the effects of mutation of Leu597 by Val and Ala in the peroxidation of arachidonic acid catalyzed by rabbit 15-lipoxygenase. Mutation of bulky Leu597 to a shorter Val residue diminishes the regiospecificity and maintains stereospecificity, but mutation to Ala, a residue even shorter than Val, enhances regiospecificity and inverts stereospecificity.