<p>The relationship of inflammatory cytokines with the subtypes and prognosis of stroke is not fully understood. Mendelian randomization (MR) was used to evaluate the bidirectional relationship of inflammatory cytokines with stroke subtype (both ischemic and hemorrhagic), and functional outcome of ischemic stroke (modified Rankin Scale score), using databases from Genome-wide association studies, the GISCOME study, the UK Biobank, deCODE, and ONTIME. Colocalization analysis was conducted to determine whether cytokines and stroke subtypes had associations with the same single-nucleotide polymorphism (SNP). Meta-analysis of MR was performed to prove the robustness of the causal relationship between cytokines and stroke subtypes. In addition, both two-step MR analysis and multivariate MR were utilized in mediation analysis to ascertain whether inflammatory cytokines affected stroke subtypes through their regulation of risk factors of cerebrovascular diseases. MR revealed that the genetic prediction of circulating fibroblast growth factor 5 (FGF5) was associated with an increased risk of ischemic stroke and intracranial hemorrhage, but not with the functional outcome of ischemic stroke. Colocalization analysis demonstrated that the association of FGF5 with ischemic stroke and intracranial hemorrhage was driven by the same SNPs. Meta-analyses supported the causal relationship of FGF5 with ischemic stroke and intracranial hemorrhage. Mediation analyses revealed that both essential hypertension and atrial fibrillation mediate the increased risk of ischemic stroke and intracranial hemorrhage due to FGF5. Inflammatory cytokines are associated with stroke and risk factors of cerebrovascular diseases. A high level of circulating fibroblast growth factor 5 is a potential risk factor for stroke.</p>