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Background: Migraine, seizures, and psychiatric disorders are frequently reported as “stroke mimics” in patients with negative diffusion weighted imaging (DWI) after IV-tPA. We sought to determine predictors of negative DWI in suspected stroke patients treated with IV-tPA.Methods: A retrospective case-control study encompassing all acute stroke patients treated with IV-tPA (at our hospital or "dripped and shipped") from January 2013-December 2014 was conducted. A total of 275 patients were identified with 47 negative DWI cases and 228 positive DWI controls. Variables including demographic factors, stroke characteristics, and clinical comorbidities were analyzed for statistical significance. A multivariate logistic regression was performed (SPSS-24) to identify predictors of negative DWI.Results: Approximately 17% of patients had negative DWI after IV-tPA. Compared to controls, migraine history independently predicted negative DWI (OR 5.0 95% CI 1.03-24.6, p=0.046). Increasing age (OR 0.97 95% CI 0.94-0.99, p=0.02) and atrial fibrillation (OR 0.25 95% CI 0.08-0.77 p=0.01) predicted lower probability of negative DWI. Gender, admission NIHSS, treatment location, pre-admission modified Rankin scale, diabetes mellitus, hypertension, hyperlipidemia, symptom side, seizure history, and psychiatric history did not predict negative DWI status.Conclusion: In our study, only pre-existing migraine history independently predicted negative DWI after IV-tPA treatment in suspected stroke patients. Although helpful in acute evaluation, this should not preclude treatment with IV-tPA considering the outcomes of missed strokes and low complication risk of IV-tpa in these patients.