It has been proposed that genetic factors contribute to the susceptibility of non-small cell lung cancer (NSCLC). The programmed cell death 6 interacting protein (PDCD6IP) encodes for a protein that has been known to bind to the products of the PDCD6 gene, a required protein in apoptosis. The aim of this study is to investigate the relationship between PDCD6IP insertion/deletion (I/D) polymorphism (rs28381975) and NSCLC risk in a Chinese population. A population-based case-control study was conducted in 449 NSCLC patients and 512 cancer-free controls. The genotype of the PDCD6IP gene was determined by using a polymerase chain reaction assay. The promoter activity was analyzed by luciferase reporter assay in A549 and H1299 cells. Statistically significant difference was observed when the patients and controls were compared according to ID + II versus DD (OR = 1.72, 95 % CI 1.29-2.31, P < 0.01). The I allele was significantly associated with NSCLC risk (OR = 1.41, 95 % CI 1.18-1.69, P < 0.01). Compared to TNM stage I + II, PDCD6IP I/D polymorphism significantly increased advanced NSCLC risk (OR = 2.06, 95 % CI 1.30-3.26, P < 0.01). Promoter reporter structures carrying the I allele displayed significantly higher promoter activity than the D allele in A549 and H1299 cells (P = 0.001). The results from this study suggested that PDCD6IP I/D polymorphism was potentially related to NSCLC susceptibility in Chinese Han population.