Analysis of 47,529 UK Biobank participants revealed that elevated TNF pathway proteins independently increase incident stroke risk by 14-22%, with TNF-α driving 54% higher recurrence rates in stroke survivors across four prospective cohorts. Single-cell sequencing of human carotid plaques pinpointed CD8+ T cells showing 4.1-fold TNF enrichment at vulnerable fibrous caps. This comprehensive investigation bridges population-scale epidemiology with cellular mechanisms, positioning TNF as a promising therapeutic target beyond traditional cardiovascular risk factors. The findings address a critical clinical gap, as stroke remains a leading cause of disability despite current prevention strategies. TNF-targeting biologics, already approved for autoimmune conditions, could potentially repurpose for cerebrovascular protection. However, this preprint awaits peer review, and results may change upon scientific scrutiny. The observational design cannot establish causation, and anti-TNF therapies carry infection risks that must be weighed against cardiovascular benefits. While confirmatory rather than paradigm-shifting, the multi-modal evidence strengthens the case for inflammation-targeted stroke prevention trials.