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Background: The National Institutes of Health Stroke Scale (NIHSS) score has been used to measure initial stroke severity. However, limited data are available on the utility of NIHSS in predicting all-cause mortality risk.Objective: To assess the association between stroke severity and mortality in stroke patients, using NIHSS stroke severity scoring.Methods: This retrospective cohort study followed patients after first inpatient diagnosis of stroke using OPTUM de-identified Integrated Claims-Medical Database (2007-2016). The NIHSS score was imputed using 100 clinically relevant predictors selected by a random forest method. Patients were classified by NIHSS score into 5 severity groups: no impairment (<1, NI), minor (1-5, Min), moderate (>5-16, Mod), moderately severe (>16-21, MS) or severe (>21-42, S). Patients were followed from stroke diagnosis to the earliest occurrence of either death, end of data or lost to follow-up. Time to death was assessed by Cox proportional hazard regression, comparing more severe stroke patients vs the NI patients (reference group), adjusting for age, gender, comorbidity index, and region.Results: A total of 16,554 stroke patients were studied; 17%, 57%, 22%, 2%, and 2% were in None, Min, Mod, MS and S groups, respectively. Mean age was 68 years at stroke diagnosis (ranging 64 to 79 years). Overall, 4.3% had a history of atrial fibrillation and 3.1% received anticoagulants for stroke prevention. Median follow-up was 23, 18, 10, 0.9 and 0.6 months for the None, Min, Mod, MS and S cohorts, respectively. Following stroke diagnosis, 74% of MS and 89% S patients died within 30 days of stroke onset, whereas the NI and Min patients remained alive within 30 days. When compared with the NI patients, more severe patients had significantly increased mortality risk; hazard ratios (95% confidence intervals) were 2.8 (2.2-3.6), 9.7 (7.4-12.6), 116 (86-154), and 364 (270-491) for the Min, Mod, MS and S patients, respectively.Conclusions: Mortality rates increased significantly with more severe strokes, as determined by the initial NIHSS score. Over 75% of the patients with moderately severe and severe strokes died within 1 month following stroke diagnosis.