Whether lesion volume on diffusion-weighted MRI imaging (DWI) can reliably predict functional outcome in acute ischemic stroke is controversial. The aim of our study was to assess whether the Alberta Stroke Program Early CT Score (ASPECTS) on DWI is useful for predicting functional outcome in patients with anterior circulation infarction with a broad range of severities. Three-hundred and fifty patients with first-ever ischemic stroke in the anterior circulation within 24 h of onset were enrolled. We compared background characteristics, vital signs, laboratory data, and MRI findings between favorable (F) and unfavorable (U) outcome groups at 3 months, according to the modified Rankin Scale (mRS). The F and U groups were defined as having a mRS of 0-2 and 3-6, respectively. DWI ASPECTS was scored by DWI obtained 3-24 h after onset. Two-hundred and eighteen patients (62.3%) were classified into the F group and 132 patients (37.7%) into the U group. On univariate analysis, the F group patients were younger, had lower score of the National Institutes of Health Stroke Scale (NIHSS) at entry (5.7 ± 3.3 vs. 14.2 ± 6.0), male predominance, longer time after onset, lower rate of prior antithrombotic therapy, higher hematocrit and lower fibrinogen than the U group patients. Stroke subtype was different between the two groups, and F group patients had higher DWI ASPECTS score, lower leukoaraiosis and medial temporal atrophy score, and lower rate of early neurological deterioration (END) than the U group patients. Multiple logistic regression analysis revealed that NIHSS (p< 0.001), prior antithrombotic therapy (p = 0.013), ASPECTS (p = 0.002), and END (p < 0.001) were independent predictors of functional outcome. DWI ASPECTS can be an independent predictor for functional outcome, along with other clinical variables.