SummaryObjectiveStudies have addressed the potential involvement of L‐12/15‐lipoxygenases (LOs), a polyunsaturated fatty acid metabolizing enzyme, in experimental models of acute stroke and chronic neurodegeneration; however, none to our knowledge has explored its role in epilepsy development. Thus, this study characterizes the cell‐specific expression of L‐12/15 ‐LO in the brain and examines its contribution to epileptogenesis.MethodsL‐12/15‐LO messenger RNA (mRNA) and protein expression and activity were characterized via polymerase chain reaction (PCR), immunocytochemistry and enzyme‐linked immunosorbent assay (ELISA), respectively. To assess its role in epileptogenesis, L‐12/15 ‐LO‐deficient mice and their wild‐type littermates were treated with pentylenetetrazole (PTZ, ip) every other day for up to 43 days (kindling paradigm). The innate seizure threshold was assessed by the acute PTZ‐induced seizure response of naive mice.ResultsL‐12/15 ‐LO mRNA is expressed in hippocampal and cortical tissue from wild‐type C57BL/6 mice. In addition, it is physically and functionally expressed by microglia, neurons, and brain microvessel endothelial cells, but not by astrocytes. Mice deficient in L‐12/15 ‐LO were resistant to PTZ‐induced kindling and demonstrated an elevated innate seizure threshold. Despite this, a significant increase in seizure‐related mortality was observed during the kindling paradigm in L‐12/15 ‐LO nulls relative to their wild‐type littermates.SignificanceThe present study is the first to detail the role of L‐12/15‐LO in the epileptogenic process. The results suggest that constitutive L‐12/15‐LO expression contributes to a lower innate set point for PTZ acute seizure generation, translating to higher rates of kindling acquisition. Nevertheless, increased seizure‐related deaths in mice lacking activity of L‐12/15‐LO suggests that its products may influence endogenous mechanisms involved in termination of seizure activity.