Purpose Programmed cell death 6 (PDCD6) is a calcium sensor participating in T-cell receptor-, Fas-, and glucocorticoid-induced programmed cell death. At the sites of lung tumors, the expression of PDCD6 is higher than that in non-tumor tissues. However, the contribution of variant PDCD6 genotypes to lung cancer is largely unknown. The current study aimed to evaluate the contributions of the PDCD6 rs4957014 and rs3756712 genotypes to the risk of lung cancer. Patients and methods The contributions of PDCD6 genotypes to lung cancer risk were examined among 358 patients with lung cancer and 716 age- and gender-matched healthy controls by typical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Results The results showed that the GG but not the GT genotype of PDCD6 rs4957014 was associated with a decreased risk of lung cancer (odds ratio (OR) =0.41, 95% confidence interval (CI) =0.23-0.72, p=0.0013). The analysis of allelic frequency distributions showed that the G allele of PDCD6 rs4957014 decreased lung cancer susceptibility (p=0.0090). There was no association between PDCD6 rs3756712 genotypes and lung cancer risk. Interestingly, the GG genotype at PDCD6 rs4957014 significantly decreased the risk of lung cancer among males (adjusted OR =0.29, 95% CI =0.14-0.57) and smokers (adjusted OR =0.34, 95% CI =0.18-0.61) but not among females and non-smokers. Conclusion The GG genotype of PDCD6 rs4957014 may decrease lung cancer risk in males and smokers and may serve as a practical marker for early detection and the incidence of lung cancer in Taiwan.