MRI is widely used in the assessment of acute ischemic stroke. In particular, it identifies the mismatch between hypoperfused and the permanently damaged tissue, the PWI-DWI mismatch volume. It is used to help triage patients into active or supportive treatment pathways. COMBAT Stroke is an automated software tool for estimating the mismatch volume and ratio based on MRI. Herein, we validate the decision made by the software with actual clinical decision rendered. Furthermore, we evaluate the association between treatment decisions (both automated and actual) and outcomes. COMBAT Stroke was used to determine PWI-DWI mismatch volume and ratio in 228 patients from two European multi-center stroke databases. We performed confusion matrix analysis to summarize the agreement between the automated selection and the clinical decision. Finally, we evaluated the clinical and imaging outcomes of the patients in the four entries of the confusion matrix (true positive, true negative, false negative, and false positive). About 186 of 228 patients with acute stroke underwent thrombolytic treatment, with the remaining 42 receiving supportive treatment only. Selection based on radiographic criteria using COMBAT Stroke classified 142 patients as potential candidates for thrombolytic treatment and 86 for supportive treatment; 60% sensitivity and 29% specificity. The patients deemed eligible for thrombolytic treatment by COMBAT Stroke demonstrated significantly higher rates of compromised tissue salvage, less neurological deficit, and were more likely to experience thrombus dissolving and reestablishment of normal blood flow at 24 h follow-up compared to those who were treated without substantial PWI-DWI mismatch. These results provide evidence that COMBAT Stroke, in addition to clinical assessment, may offer an optimal framework for a fast, efficient, and standardized clinical support tool to select patients for thrombolysis in acute ischemic stroke.