BACKGROUND: Heart rate variability (HRV) has been proposed as a predictor of acute stroke outcome. This study aimed to evaluate the predictive value of a novel non-linear method for analysis of HRV, multiscale entropy (MSE) and outcome of patients with acute stroke who had been admitted to the intensive care unit (ICU). METHODS: The MSE of HRV was analysed from 1 h continuous ECG signals in ICU-admitted patients with acute stroke and controls. The complexity index was defined as the area under the MSE curve (scale 1-20). A favourable outcome was defined as modified Rankin scale 0-2 at 3 months after stroke. RESULTS: The trends of MSE curves in patients with atrial fibrillation (AF) (n=77) were apparently different from those in patients with non-AF stroke (n=150) and controls (n=60). In addition, the values of complexity index were significantly lower in the patients with non-AF stroke than in the controls (25.8+/-.3 vs. 32.3+/-4.3, p<0.001). After adjustment for clinical variables, patients without AF who had a favourable outcome were significantly related to higher complexity index values (OR=1.15, 95% CI 1.07 to 1.25, p<0.001). Importantly, the area under the receiver operating characteristic curve for predicting a favourable outcome of patients with non-AF stroke from clinical parameters was 0.858 (95% CI 0.797 to 0.919) and significantly improved to 0.903 (95% CI 0.853 to 0.954) after adding on the parameter of complexity index values (p=0.020). CONCLUSIONS: In ICU-admitted patients with acute stroke, early assessment of the complexity of HRV by MSE can help in predicting outcomes in patients without AF.