We found that genetically downregulated IL‐6 signaling was associated with small vessel stroke in the earlier GWAS from MEGASTROKE (OR, 0.85 [95% CI, 0.77–0.95]; P=0.003), but this association was attenuated in the larger GIGASTROKE data set (OR, 0.93 [95% CI, 0.82–1.06]; P=0.28), which is more enriched with MRI‐confirmed lacunar stroke cases. Here, IL6 is linked to small vessel stroke.