Background and Purpose— The 15-deoxy Δ prostaglandin J ₂ (15-dPGJ ₂ ) is an anti-inflammatory prostaglandin that has been proposed to be the endogenous ligand of peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor that can exert potent anti-inflammatory actions by repressing inflammatory genes when activated. It has been suggested that 15-dPGJ ₂ could be beneficial in neurological disorders in which inflammation contributes to cell death such as stroke. Methods— We investigated the relationship between plasma levels of 15-dPGJ ₂ and early neurological deterioration (END), infarct volume, and neurologic outcome in 552 patients with an acute stroke admitted within 24 hours after symptoms onset. Results— Median [quartiles] plasma 15-dPGJ ₂ levels on admission were significantly higher in patients than in controls (60.5 [11.2 to 109.4] versus 5.0 [3.8 to 7.2] pg/mL; P <0.0001). Levels of this prostaglandin were also significantly higher in patients with vascular risk factors (history of hypertension or diabetes) and with atherothrombotic infarcts (113.9 [81.6 to 139.7] pg/mL), than in those with lacunar (58.7 [32.7 to 86.2] pg/mL), cardioembolic (12.1 [6.5 to 39.2] pg/mL), or undetermined origin infarcts (11.4 [5.6 to 24.3] pg/mL) ( P <0.0001). In the subgroup of patients with atherothrombotic infarcts, the adjusted odds ratio of END and poor outcome for 1 pg/mL increase in 15-dPGJ ₂ were 0.95 (95% CI, 0.94 to 0.97) and 0.97 (95% CI, 0.96 to 0.98), respectively. In a generalized linear model, by 1 U increase in 15-dPGJ ₂ , there was a reduction of 0.47 mL (95% CI, 0.32 to 0.63) in the mean estimated infarct volume. Conclusions— Increased plasma 15-dPGJ ₂ concentration is associated with good early and late neurological outcome and smaller infarct volume. These findings suggest a neuroprotective effect of 15-dPGJ ₂ in atherothrombotic ischemic stroke.