Previous studies reported associations of IFITM3 SNP rs12252 with severe influenza, but evidence of association and the mechanism of risk remains controversial. We prioritized SNPs in IFITM3 based on putative biological function and identified rs34481144 in the 5′ UTR. We found evidence of a novel association of rs34481144 with severe influenza in three influenza-infected cohorts characterized by different levels of influenza illness severity. We determined the role of rs34481144 as an expression quantitative trait loci (eQTL) for IFITM3, with the risk allele associated with lower mRNA expression. The risk allele was found to have decreased IRF3 binding and increased CTCF binding in promoter-binding assays, and risk allele carriage diminished transcriptional correlations among neighboring genes, indicative of CTCF boundary activity. Furthermore, the risk allele disrupts a CpG site that undergoes differential methylation in CD8 T-cell subsets. Carriers of the risk allele had reduced CD8 T-cells in their airways during natural influenza infection, consistent with IFITM3 promoting airway CD8 T-cell accumulation, indicating that a critical function for IFITM3 may be to promote immune cell persistence at mucosal sites. Our study identifies a new regulator of IFITM3 expression that associates with CD8 T-cell levels in the airways and a spectrum of clinical outcomes.