Exposure to tobacco smoke as well as environmental and occupational factors is the major cause of lung cancer. Non-small cell lung cancer (NSCLC) is the major histological type. Genes in pathways affecting inflammation, cellular stress and apoptosis are important, and the extent of inflammation in the lung could be affected by polymorphisms modifying these responses. In the present study we have investigated whether a combination of potential functional polymorphisms in genes related to inflammation may modulate risk of NSCLC. Eleven functional polymorphisms in nine genes were analyzed for association with risk of NSCLC in 882 subjects from the Norwegian population. The results showed that individuals carrying combination of three functional polymorphisms in the caspase-8, matrix metalloproteinase-1, seleno-protein S1, and interleukin-10 genes had two-fold increased risk of NSCLC (OR 2.06 (95% CI, 1.19–3.47) whereas individuals with four risk genotypes had 4.62-fold increased risk (OR 4.62, 95% CI, 1.69–12.63). These results highlight the need to investigate the combinatory effects of multiple SNPs in the carcinogenesis of the lung.