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. Method: A retrospective case-control study encompassing all acute stroke patients treated with IV-tPA (at our hospital or “dripped and shipped”) from January 2013 to December 2014 was con- ducted. 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 (odds ratio [OR] 5.0 95% confidence interval [CI] 1.03-24.6, P = .046). Increasing age (OR .97 95% CI .94-.99, P = .02) and atrial fibrillation (OR .25 95% CI .08-.77, P = .01) predicted lower probability of negative DWI. Gender, admission NIHSS, treatment location, preadmission modified Rankin scale, diabetes mellitus, hypertension, hyperlipidemia, symptom side, seizure history, and psychiatric history did not predict negative DWI status. Conclusions: In our study, roughly 1 in 6 patients treated with IV-tPA were later found to be stroke mimics with negative DWI. Despite a high proportion of suspected stroke mimics in our study, only preexisting migraine history independently predicted negative DWI status after IV-tPA treatment in suspected stroke patients.