We examined associations between single-nucleotide polymorphisms (SNPs) ofIFITM3,TLR3, andCD55 genes and influenza clinical outcomes in Chinese. A multicenter study was conducted on 275 adult cases of avian (H7N9) and pandemic (H1N1(pdm09)) influenza. Host DNA was extracted from diagnostic respiratory samples;IFITM3 rs12252,TLR3 rs5743313,CD55 rs2564978, andTLR4 rs4986790/4986791 were targeted for genotyping (Sanger sequencing). The primary outcome analyzed was death. IFITM3 andTLR3 SNPs were in Hardy-Weinberg equilibrium; their allele frequencies (IFITM3/C-allele 0.56, TLR3/C-allele 0.88) were comparable to 1000 Genomes Han Chinese data. We found over-representation of homozygousIFITM3 CC (54.5% vs 33.2%;P = .02) andTLR3 CC (93.3% vs 76.9%;P = .04) genotypes among fatal cases. Recessive genetic models showed their significant independent associations with higher death risks (adjusted hazard ratio [aHR] 2.78, 95% confidence interval [CI] 1.29-6.02, and aHR 4.85, 95% CI 1.11-21.06, respectively). Cumulative effects were found (aHR 3.53, 95% CI 1.64-7.59 per risk genotype; aHR 9.99, 95% CI 1.27-78.59 with both). Results were consistent for each influenza subtype and other severity indicators. TheCD55 TT genotype was linked to severity. TLR4 was nonpolymorphic. Host genetic factors may influence clinical outcomes of avian and pandemic influenza infections. Such findings have important implications on disease burden and patient care in at-risk populations.