Irisin was discovered as a PGC-1a-activated messenger of myocytes that links sedentary lifestyle, obesity, and diabetes. In this study, we investigated the short-term prognostic value of early measurement of irisin concentration in 1530 Han Chinese patients with acute ischemic stroke (AIS) from three stroke centers. The subjects were the first-ever AIS patients who were hospitalized at three stroke centers during the period from January 2015 to December 2016. Clinical information and stroke severity were collected at admission. Neurological evaluations were conducted at the 6-month follow-up. Serum levels of irisin, National Institutes of Health Stroke Scale (NIHSS), and conventional risk factors were evaluated to determine their value to predict functional outcome and mortality within 6months. Multivariate analyses were performed using logistic regression models. During follow-up, a poor functional outcome was found in 588 patients (38.4%; 95% confidence interval (CI), 36.0-40.9%), and 325 patients died (21.2%; 95% CI, 19.2-23.3%). The stroke patients included in the study were divided into four groups according to irisin quartiles (first is the lowest level). Poor outcome across the irisin quartiles ranged from 54.5% (first quartile) to 21.7% (fourth quartile), and mortality rate ranged from 39.3% (first quartile) to 6.3% (fourth quartile). In a multivariate model using the first quartile (Q1) of irisin vs. Q2-Q4 together with the clinical variables, the marker displayed prognostic information and increased odds ratios of poor outcome by 58% (OR for Q1, 1.58 [95% CI, 1.12-2.43]) and mortality by 185% (OR for Q1, 2.85 [95% CI, 1.79-4.02]). In addition, a model containing known risk factors plus irisin compared with a model containing known risk factors without irisin showed a greater discriminatory ability to predict poor outcome (the area under the curve (AUC) with an increase from 0.73 to 0.75 [95% CI, 0.70-0.81]) and mortality (the AUC increased from 0.80 to 0.83 [95% CI, 0.78-0.87]). Irisin is a novel, independent prognostic marker improving currently used risk stratification of stroke patients. Further studies are needed to confirm this association, which may pave the way to new therapeutic options.