Background We aimed to compare outcomes after stroke due to anterior circulation large vessel occlusion with initial imaging assessments using diffusion‐weighted imaging (DWI) or noncontrast computed tomography (NCCT). Methods Among 2399 patients with large vessel occlusion stroke in a prospective, multicenter registry, patients with (1) prestroke modified Rankin Scale scores 0 to 1, (2) occlusion of the internal carotid artery or M1 segment of the middle cerebral artery, and (3) onset‐to‐hospital‐arrival time <6 hours were included. The primary effectiveness outcome was good functional outcome, defined as modified Rankin Scale scores 0 to 2 at 3 months. Safety outcomes included symptomatic intracranial hemorrhage. Intergroup biases were accounted for by mixed‐effects multivariable modeling and inverse probability of treatment weighting. Results A total of 343 patients (130 women [37.9%]; median age, 74 years [interquartile range, IQR, 66–82 years]) were analyzed. DWI‐based assessment was performed in 217 patients, and NCCT‐based assessment was performed in 126 patients. The DWI group showed a lower baseline National Institutes of Health Stroke Scale score ( P <0.01) and lower Alberta Stroke Program Early CT Score ( P <0.01) than the NCCT group. Frequency of endovascular therapy was lower in the DWI group (71.9%) than in the NCCT group (84.1%; P <0.01). Median hospital‐arrival‐to‐arterial‐puncture time was 55 minutes (IQR, 40–77.5 minutes) in the DWI group and 55 minutes (IQR, 35–80 minutes) in the NCCT group ( P =0.89), with similar rates of successful recanalization (77.6% versus 76.4%, respectively; P =0.88). Frequency of good functional outcome was 47.0% in the DWI group and 41.3% in the NCCT group (adjusted odds ratio, 1.32; 95% CI, 0.49–3.55). Symptomatic intracranial hemorrhage was encountered in 2.8% in the DWI group and 1.6% in the NCCT group ( P =0.71). Conclusions Potential difference in accuracy of ischemic damage assessment between the 2 modalities did not seem to affect outcomes of anterior circulation large vessel occlusion stroke. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02419794.