α-dioxygenases (α-DOXs) catalyze the primary oxygenation of fatty acids into a newly identified group of oxylipins. Here we show that expression of the Arabidopsis α-DOX1 gene is induced in response to both incompatible and compatible bacterial infections. However, the level of α-DOX1 mRNA and dioxygenase activity appears earlier and reaches higher values when infection promotes a hypersensitive reaction. Furthermore, whereas gene expression is confined to necrotic lesions during the hypersensitive response, it occurs throughout the chlorotic area during a compatible interaction. Accumulation of α-DOX1 transcripts is impaired in SA-compromised plants and induced by SA and by chemicals generating nitric oxide (NO), intracellular superoxide or singlet oxygen, three signals mediating host cell death. Transgenic plants with altered levels of α-dioxygenase react like wild-type plants to a compatible pathogen. In contrast, plants with reduced activity develop a more rapid and severe necrotic response than wild-type plants to incompatible bacteria and paraquat treatment, respectively, and a milder response when α-DOX1 is overproduced. Our results suggest that plant α-dioxygenases are used to generate lipid-derived molecules for a process that protects plant tissues from oxidative stress and cell death.