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Background and Purpose: Acute rehabilitation is known to enhance stroke recovery. However, poststroke lethargy and fatigue can hinder participation in rehabilitation therapies. We hypothesized that in patients with moderate to severe stroke complicated by poststroke fatigue and lethargy early stimulant therapy with modafinil increases favorable discharge disposition defined as transfer to acute inpatient rehabilitation or home.Methods: We retrospectively reviewed a cohort of patients with acute stroke admitted to the stroke service over a 3-year period. All patients 18 years or older with confirmed ischemic or hemorrhagic stroke, an NIHSS greater than or equal to 5 and documentation of fatigue/lethargy in clinical documentation were included. We compared patients that were treated with modafinil 50-200 mg to those managed with standard care. The primary outcome measure was discharge disposition. Secondary outcome was 90 day modified Rankin score (mRS). Statistical significance was determined using chi-square test for association and logistic regression models. Logistic regression models were derived in 2 ways with both raw data and an adjusted model that accounted for age, sex, and NIHSS score to account for the lack of randomization.Results: This study included 199 stroke patients (145 ischemic, 54 hemorrhagic). Seventy-two (36.2%) were treated with modafinil and 129 (64.8%) were discharged to acute inpatient rehabilitation, while none were recommended for discharge home. Median NIHSS for modafinil patients was 13.5 versus 11 for standard care patients (P = .059). In adjusted models, modafinil was associated with higher odds of favorable discharge disposition (OR 2.00, 95% CI 1.01-3.95). Favorable outcome at 90 days defined as mRS less than or equal to 2 occurred more frequently with modafinil (5.6% versus 3.3%) but this did not achieve statistical significance (P > .1). These results occurred despite the modafinil group requiring longer ICU stays and having more in-hospital complications such as infections and need for percutaneous gastrostomy tubes. The benefit of modafinil was seen across all subgroups except those with severe stroke (NIHSS ≥ 15). There were no significant adverse events associated with modafinil administration.Conclusions: Modafinil use in acute in-hospital stroke patients with moderate stroke complicated by lethargy and fatigue was associated with improved discharge disposition. Randomized controlled trials are needed to further study the safety, efficacy, and long-term effects of modafinil in this patient population. [ABSTRACT FROM AUTHOR]