Complement factor I (CFI) plays an important role in the development of non-small cell lung cancer (NSCLC). This study aims to examine the association of CFI genetic variants with the risk of developing NSCLC in Chinese population. A hospital-based case-control study was conducted in 470 patients with NSCLC and 470 controls in Chinese population. Totally, 13 tag single nucleotide polymorphisms (tag SNPs) of CFI were selected by Haploview software using the HapMap database. Genotyping was performed using iPLEX Gold Genotyping Assay and Sequenom MassARRAY. The odds ratios (ORs) and 95% confidence interval (95% CI) were calculated by logistic regression model. Our results showed that individuals with rs6822976 GG genotype had a significant decreased risk of NSCLC (OR = 0.64; 95% CI = 0.42-0.98) when compared with rs6822976 AA genotype carriers. We also found that rs7671905 TT genotype exhibited a significant decreased risk of NSCLC compared with CC genotype with OR (95% CI) of 0.55 (0.33-0.91). There was no significant association between other selected SNPs and the risk of NSCLC. When stratified by smoking status, the decreased risk of NSCLC was observed to be associated with the genotype with at least one rs6822976 G allele among non-smokers (OR = 0.66; 95% CI = 0.47-0.93), but not among smokers (OR = 1.01; 95% CI = 0.67-1.53). For CFI rs7671905 polymorphism, the individuals with at least one T allele have a decreased risk of NSCLC with OR (95 % CI) of 0.71 (0.51-0.99), but not among smokers (OR = 0.93; 95% CI = 0.61-1.41). When stratified by age, we found that rs7671905 TT genotype has contributed to the decreased risk of NSCLC among older subjects with OR (95% CI) of 0.46 (0.23-0.95), but not among younger subjects with OR (95% CI) of 0.64 (0.31-1.34) (P(interaction) = 0.03). After stratifying by sex, our study showed that rs7671905 TT genotype was related to the risk of NSCLC among males (OR = 0.53; 95% CI = 0.29-0.98), but not among females (OR = 0.62; 95% CI = 0.25-1.57) (P(interaction) = 0.03). CFI genetic variants played an important role in the development of NSCLC in Chinese population.