Background: The National Institutes of Health Stroke Scale (NIHSS) was created to detect treatment related differences in clinical trials and was designed to measure right and leftsided cerebral hemispheric function. Objective: To valid ate the original design in patients with very large strokes. Design: A previousl y published factor structure was fit to the data. Then, a new analysis was condu cted to explore the underlying structure of the scale in this population. Finall y, NIHSS scores and infarction volumes were compared. Setting: The Clomethiazole for Acute Stroke Study Ischemic, conducted in academic and community hospitals . Patients: Individuals with acute stroke seen within 12 hours of onset. Of 1191 records available, 98%had complete NIHSS scores. Main Outcome Measure: Goodnes s of fit statistic (Bentler) for each factor solution. Results: Two factors we re found underlying the NIHSS, corresponding to the left and right hemispheres ( goodness of fit = 0.97), using the previously published factor analysis. The new exploratory analysis also suggested 2 factors representing left and right brain function. The median (range) NIHSS scores were 15 (5-25) for right brain strok es and 19 (6-32) for left brain strokes (P<.001). The median (range) infarction volumes were 56.2 mL (0.1-381.5 mL) for right brain strokes and 37.8 mL (0.2- 255.1 mL) for left brain strokes (P<.001). The correlation coefficient between N IHSS score and lesion volume was 0.37 (P<.001). Conclusions: The underlying stru cture of the NIHSS conforms to cerebral hemispheric lateralization, confirming p revious findings in a new population of large hemispheric strokes. Left brain s trokes score 4 points higher on the NIHSS than right brain strokes of larger vol ume. Background: The National Institutes of Health Stroke Scale (NIHSS) was created to detect treatment related differences in clinical trials and was designed to measure right and leftsided cerebral hemispheric function. Objective: To valid ate the original design in patients with very large strokes. Design : A new analysis was condu cted to explore the underlying structure of the scale in this population. Finall y, NIHSS scores and infarction volumes were compared. Setting: The Clomethiazole for Acute Patients: Individuals with acute stroke seen within 12 hours of onset. Of 1191 records available, 98% had complete NIHSS scores. Main Outcome Measure: Goodnes s of fit statistic (Bentler) for each factor solution. Results: Two factors we re found underlying the NIHSS, corresponding to the left and right hemispheres (goodness of fit = 0.97), using the previ The new exploratory analysis also suggested 2 factors representing left and right brain function. The median (range) NIHSS scores were 15 (5-25) for right brain strokes and 19 (6-32) for left brain strokes (P <.001). The median (range) infarction volumes were 56.2 mL (0.1-381.5 mL) for right brain strokes and 37.8 mL (0.2-255.1 mL) for left brain strokes (P <.001) between N IHSS score and lesion volume was 0.37 (P <.001). Conclusions: The underlying stru cture of the NIHSS conforms to cerebral hemispheric lateralization, confirming p revious findings in a new population of large hemispheric strokes. Left brain s trokes score 4 points higher on the NIHSS than right brain strokes of larger vol ume.