Objectives: Vulnerability to brain injury in infants with congenital heart disease (CHD) may differ by CHD lesion. However, the link between arterial ischemic stroke (AIS) and neurodevelopment, and whether it differs by CHD lesion, is unknown. We sought to determine whether: (1) Stroke topology differs between infants with Transposition of the Great Arteries (TGA) and single ventricle physiology (SVP), and relationship with neurodevelopment;(2) Associations between stroke volume and neurodevelopment are CHD lesion specific. Methods: 64 of 312 CHD infants (TGA n=38, SVP n=26) studied prospectively with pre- and/or post-operative brain MRIs had AIS. AIS were segmented on 3DT1 and/or ADC images. 39 infants completed 18-month neurodevelopmental assessments with Bayley Scales (2 ^nd or 3 ^rd Edition); scores were adjusted to account for differences between versions. Adverse neurodevelopment was defined as <85 points. We used multivariable linear regression models to study associations between AIS volume and neurodevelopment, stratifying by CHD lesion and adjusting for study site. Probability maps demonstrating areas vulnerable to AIS and odds ratio maps reflecting likelihood of a lesion predicting adverse outcomes were developed. Results: Most AIS were in MCA territories, with a left-sided predominance (Fig 1A). Stroke volume did not differ between CHD groups (p=0.8). Basal ganglia lesions were most predictive of cognitive (max OR=11) and motor (max OR=6) outcomes (Fig 1B). Stratifying by CHD lesion, AIS volume predicted 18-month cognitive outcomes in infants with TGA (β=-0.6, 95%CI -1.0-(-0.1), p=0.02) but not SVP (β=7.9, 95%CI -72-88). AIS volume did not predict motor outcomes in infants with TGA (β=-0.6, 95%CI -1.6-0.3) or SVP (β=-19.7, 95%CI -91-52). Conclusions: Neonatal AIS topology does not differ between infants with TGA and SVP. AIS location and size are important predictors of neurodevelopment at 18 months though this association differs by CHD lesion.