12/15-lipoxygenase (12-15LO) is a lipid-peroxidizing enzyme widely expressed in the central nervous system where it has been involved in the neurobiology of Alzheimer's disease (AD) because it modulates amyloid beta (Aβ) and APP processing. However, its biological effect on tau protein is unknown. We investigated the effect of 12-15LO on tau levels and metabolism in vivo and in vitro and the mechanism involved by using genetic and pharmacologic approaches. While no significant differences were observed in the levels of total tau for both groups, compared with controls, Tg2576 mice overexpressing 12-15LO had elevated levels of phosphorylated tau at two specific epitopes, Ser 202/Thr 205 and Ser 396. In vitro and in vivo studies show that 12-15LO modulates tau metabolism specifically via the cdk5 kinase pathway. Associated with these changes were biochemical markers of synaptic pathology. Finally, 12-15LO-dependent alteration of tau metabolism was independent from an effect on Aβ. Our findings reveal a novel pathway by which 12-15LO modulates endogenous tau metabolism making this protein an appealing pharmacologic target for treatment of AD and related tauopathies.