The genetic predisposition to severe A(H1N1)pdm09 influenza was evaluated in 409 patients including 162 severe cases and 247 mild controls. We prioritized candidate variants based on the result of a pilot GWAS and a lung eQTL dataset. The GG genotype of rs2070788, a higher-expression variant of TMPRSS2, was a risk variant (OR 2.11, 95% CI 1.18～3.77, P=0.0113) to severe A(H1N1)pdm09 influenza. A potentially functional SNP, rs383510, accommodated in a putative regulatory region was identified to tag rs2070788. Luciferase assay results showed the putative regulatory region was a functional element, in which rs383510 regulated TMPRSS2 expression in a genotype-specific manner. Notably, rs2070788 and rs383510 were significantly associated with the susceptibility to A(H7N9) influenza in 102 A(H7N9) patients and 106 healthy controls. Therefore, we demonstrate that genetic variants with higher TMPRSS2 expression confer higher risk to severe A(H1N1)pdm09 influenza. The same variants also increase the susceptibility to human A(H7N9) influenza.