Background and Purpose— The genetic relationships between stroke risk, stroke severity, and early neurological changes are complex and not completely understood. Genetic studies have identified 32 all stroke risk loci. Polygenic risk scores can be used to compare the genetic architecture of related traits. In this study, we compare the genetic architecture of stroke risk, stroke severity, and early neurological changes with that of 2 stroke risk factors: type 2 diabetes mellitus (T2DM) and hypertension. Methods— We assessed the degree of overlap in the genetic architecture of stroke risk, T2DM, hypertension, and 2 acute stroke phenotypes based on the National Institutes of Health Stroke Scale (NIHSS), which ranges from 0 for no stroke symptoms to 21 to 42 for a severe stroke: baseline (within 6 hours after onset) and change in NIHSS (ΔNIHSS=NIHSS at baseline−NIHSS at 24 hours). This was done by (1) single-nucleotide polymorphism by single-nucleotide polymorphism comparison, (2) weighted polygenic risk scores with sentinel variants, and (3) whole-genome polygenic risk scores using multiple P thresholds. Results— We found evidence of genetic architecture overlap between stroke risk and T2DM ( P =2.53×10 ^{− 169} ), hypertension ( P =3.93×10 ^{− 04} ), and baseline NIHSS ( P =0.03). However, there was no evidence of overlap between ΔNIHSS and stroke risk, T2DM, or hypertension. Conclusions— The genetic architecture of stroke risk is correlated with that of T2DM, hypertension, and initial stroke severity (NIHSS within 6 hours of stroke onset). However, the genetic architecture of early neurological change after stroke (ΔNIHSS) is not correlated with that of ischemic stroke risk, T2DM, or hypertension. Thus, stroke risk and early neurological change after stroke have distinct genetic architectures.