Chronic obstructive pulmonary disease (COPD) is a systemic obstructive lung disease which worsens over time. Recent studies indicate that COPD is one of the most common causes of death worldwide and that it follows closely cardiovascular and malignant diseases. It is believed that the primary risk factor for COPD is tobacco smoking, which is similar to lung cancer, but only a certain percentage of those who are smokers develop the disease. This shows that there could be other additional risk factors such as an individual genetic background. Acute exacerbations, hallmark of patients who suffer from COPD, are often related to viral and bacterial infections. On the other hand, lung cancer, which has already been related to uncontrolled local and systemic inflammation, is the most common comorbidity reported in patients with COPD. The goal of this research was to explore if there is a genetic linkage of the polymorphisms rs352139 TLR9 gene and rs425154 IRAK4 gene with occurrence and development of lung cancer in COPD patients. We wanted to know which genetic changes, within the COPD subject group, could be responsible for the occurrence of lung cancer, which is the most common comorbidity in patients with COPD (30%), and if these genetic changes could be found among genes which participate in the activation and regulation of the immune response. For this purpose we analyzed the distribution of genotypes of TLR9 and IRAK4 genes within the indicated subject groups. Gender and age possible effect were also included. Our results show that there is a significant difference in distribution of the A/G genotype and allele A of polymorphism rs352139 TLR9 gene among patients with COPD and those with COPD together with lung cancer.