Purpose: To test whether the relationship between acute ischemic infarct size on concurrent computed tomographic (CT) angiography source images and diffusion-weighted (DW) magnetic resonance images is dependent on the parameters of CT angiography acquisition protocols. Materials and Methods: This retrospective study had institutional review board approval, and all records were HIPAA compliant. Data in 100 patients with anterior-circulation acute ischemic stroke and large vessel occlusion who underwent concurrent CT angiography and DW imaging within 9 hours of symptom onset were analyzed. Measured areas of hyperintensity at acute DW imaging were used as the standard of reference for infarct size. Information regarding lesion volumes and CT angiography protocol parameters was collected for each patient. For analysis, patients were divided into two groups on the basis of CT angiography protocol differences (patients in group 1 were imaged with the older, slower protocol). Intermethod agreement for infarct size was evaluated by using the Wilcoxon signed rank test, as well as by using Spearman correlation and Bland-Altman analysis. Multivariate analysis was performed to identify predictors of marked (≥20%) overestimation of infarct size on CT angiography source images. Results: In group 1 ( n = 35), median hypoattenuation volumes on CT angiography source images were slightly underestimated compared with DW imaging hyperintensity volumes (33.0 vs 41.6 mL, P = .01; ratio = 0.83), with high correlation ( ρ = 0.91). In group 2 ( n = 65), median volume on CT angiography source images was much larger than that on DW images (94.8 vs 17.8 mL, P < .0001; ratio = 3.5), with poor correlation ( ρ = 0.49). This overestimation on CT angiography source images would have inappropriately excluded from reperfusion therapy 44.4% or 90.3% of patients eligible according to DW imaging criteria on the basis of a 100-mL absolute threshold or a 20% or greater mismatch threshold, respectively. Atrial fibrillation and shorter time from contrast material injection to image acquisition were independent predictors of marked (≥20%) infarct size overestimation on CT angiography source images. Conclusion: CT angiography protocol changes designed to speed imaging and optimize arterial opacification are associated with significant overestimation of infarct size on CT angiography source images.