The most common substrate of mammalian lipoxygenases (LOXs) is arachidonic acid (AA). However, 15-LOXs can present dual substrate specificity. These LOXs catalyze the peroxidation of AA, initiated by a H-abstraction step (mainly H-13-abstraction) by the Fe(III)-OH- cofactor, and the peroxidation of linoleic acid (LA) after H-11-abstraction. In this paper, QM(B3LYP)/MM(CHARMM) calculations of the rate-limiting H-11-abstraction process of LA catalyzed by rabbit 15-LOX-1 (15-rLOX-1) have been carried out using a complete model of the solvated 15-rLOX-1:LA complex. A total of 26 QM/MM potential energy profiles as a function of the H-transfer reaction coordinate have been computed along with one QM/MM free energy profile obtained using the Free Energy Perturbation method. The molecular origin of substrate specificity of 15-rLOX-1 for LA in comparison with AA has been analyzed. In many of the QM/MM reactive 15-rLOX-1:LA energy minima, LA adopts more elongated conformations than AA, although having a shorter carbon chain, because LA has one double bond between C-1 and C-11 whereas AA has three double bonds between C-1 and C-13. Consequently, C-11 of LA can be located in the same region of the active site as C-13 of AA, a zone where H-11-abstraction from LA as well as H-13-abstraction from AA is not hindered by bulky residue side chains. This explains at a molecular level how 15-LOXs might accommodate and recognize for catalysis two substrates that are different in length by two carbons. Our results also explain why (9Z,11E)-13-hydro(pero)xyoctadeca-9,11-dienoicacid is the major product of the peroxidation and why LA is the preferential substrate of 15-rLOX-1.