Laboratory-based studies showed that host immune genes could influence the prognosis of non-small-cell lung cancer (NSCLC). Therefore, genetic polymorphisms in host immune genes may serve as predictors for NSCLC clinical outcome. To test the hypothesis that functional single nucleotide polymorphisms (SNPs) in host immune genes are associated with the prognosis of NSCLC, we systematically performed a genotyping analysis for a total of 178 SNPs from 52 immune genes in a prospective case cohort of 568 NSCLC patients. Among the 178 SNPs, 24 were significantly associated with NSCLC prognosis in different genetic models and four of them were remained in the final predictive model after multivariate stepwise Cox regression, including IL-5R rs11713419 (5′-untranslated region, 5′-UTR) (P = 0.001), IL23R rs6682925 (5′-flanking region, 5′-FR) (P = 0.017), TLR1 rs5743551 (5′-FR) (P = 0.02) and TLR3 rs3775291 (Leu412Phe) (P = 0.01). We then put the above four SNPs together, and found that the risk of death was significantly increased by 124% (HR = 2.24, 95% CI: 1.33–3.75) for the patients carrying “1” unfavorable locus and by 175% (HR = 2.75, 95% CI: 1.67–4.51) for those carrying “2-4” unfavorable loci. The risk score model and time-dependent ROC analyses further support the four SNPs and clinical risk score model. The area under curve (AUC) at year 5 increased from 0.484 to 0.831 after combining the four SNPs risk score with clinical risk score. These findings indicate that potentially functional polymorphisms in immune genes may serve as prognostic markers of clinical outcome of NSCLC.