Observational studies have shown an association between post-traumatic stress disorder (PTSD) and ischemic stroke (IS) but given the susceptibility to confounding it is unclear if these associations represent causal effects. Mendelian randomization (MR) facilitates causal inference that is robust to the influence of confounding. Using two sample MR, we investigated the causal effect of genetic liability to PTSD on IS risk. Ancestry-specific genetic instruments of PTSD and four quantitative sub-phenotypes of PTSD, including hyperarousal, avoidance, re-experiencing, and total symptom severity score (PCL-Total) were obtained from the Million Veteran Programme (MVP) using a thresholdPvalue (P)of <5 × 10−7, clumping distance of 1000 kilobase (Mb) andr2< 0.01. Genetic association estimates for IS were obtained from the MEGASTROKE consortium (Ncases= 34,217,Ncontrols= 406,111) for European ancestry individuals and from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) (Ncases= 3734,Ncontrols= 18,317) for African ancestry individuals. We used the inverse-variance weighted (IVW) approach as the main analysis and performed MR-Egger and the weighted median methods as pleiotropy-robust sensitivity analyses. In European ancestry individuals, we found evidence of an association between genetic liability to PTSD avoidance, and PCL-Total and increased IS risk (odds ratio (OR)1.04, 95% Confidence Interval (CI) 1.007–1.077,P= 0.017 for avoidance and (OR 1.02, 95% CI 1.010–1.040,P= 7.6 × 10−4for PCL total). In African ancestry individuals, we found evidence of an association between genetically liability to PCL-Total and reduced IS risk (OR 0.95 (95% CI 0.923–0.991,P= 0.01) and hyperarousal (OR 0.83 (95% CI 0.691–0.991,P= 0.039) but no association was observed for PTSD case-control, avoidance, or re-experiencing. Similar estimates were obtained with MR sensitivity analyses. Our findings suggest that specific sub-phenotypes of PTSD, such as hyperarousal, avoidance, PCL total, may have a causal effect on people of European and African ancestry’s risk of IS. This shows that the molecular mechanisms behind the relationship between IS and PTSD may be connected to symptoms of hyperarousal and avoidance. To clarify the precise biological mechanisms involved and how they may vary between populations, more research is required.