Genetically downregulated IL-6 signaling through IL6 perturbation was associated with lower odds of CAD (OR per 24% decrease in CRP of 0.92, 95% CI 0.88 to 0.95), PAD (OR of 0.80, 95% CI 0.74 to 0.87), IS (OR of 0.92, 95% CI 0.88 to 0.97) mainly driven by the large artery atherosclerotic subtype (OR of 0.75, 95% CI 0.64 to 0.88) and ultrasound-defined carotid plaque (OR of 0.82, 95% CI 0.71 to 0.95). Here, IL6 is linked to peripheral arterial disease.