Background The prognostic value of the level of interleukin (IL)-18 in patients after acute ischemic stroke (IS) has not been completely investigated. This prospective cohort study examined whether the circulating IL-18 level can predict 90-day outcome of IS. Methods and Results Plasma IL-18 level was obtained from blood samples taken by venous access at 48 h following acute IS in 217 consecutive patients. Plasma IL-18 level was also evaluated in 20 healthy and 40 at-risk control subjects. Plasma levels of IL-18 and white blood cell (WBC) counts were significantly higher in IS patients than in both control groups (all p values <0.0001). Patients with high IL-18 level (≥780 pg/ml) had significantly higher incidences of 90-day recurrent stroke and 90-day accumulative death (all p values <0.01). Univariate analysis demonstrated that IL-18 level (≥780 pg/ml), modified Rankin scale score, WBC count, creatinine level, and coronary artery disease were significantly associated with 90-day major adverse clinical outcomes (MACO) (defined as combined 90-day recurrent stroke and 90-day mortality) (all p values <0.05). Multiple stepwise logistic regression analysis demonstrated that high IL-18 level (≥780 pg/ml) (p<0.0001), together with creatinine level (p=0.024), were independently predictive of 90-day MACO. Conclusions Plasma IL-18 level is a major independent inflammatory predictor of 90-day MACO in IS patients. Evaluation of circulating IL-18 level might improve the prediction of unfavorable clinical outcome following IS. (Circ J 2007; 71: 1691 - 1696)