Background: Chronic obstructive pulmonary disease (COPD) is one of the most important causes of morbidity and mortality worldwide, characterized by persistent and progressive airflow limitations. The etiology seems to be an interaction between genetic and environmental factors. Objectives: In this study, we aimed to identify the possible association of IL-13 (-1055 C/T) and CYP1A1 (MspI) gene polymorphisms with COPD in Egyptian patients and their relation to the severity of the disease. Methodology: Our study included 200 participants (100 COPD patients and 100 controls). Pulmonary function tests were performed for patients, DNA extraction was done and the polymorphisms were analyzed using polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) for serum samples from all participants. Results: IL- 13 -1055 C/T polymorphism was significantly associated with COPD; CT and TT genotypes (P=0.01, 0.03 respectively) compared to CC genotype, with a significant association of the T allele with the disease (P=0.003), while CYP1A1 MspI polymorphism showed no significantly different distribution between patients and controls (P=0.11& 0.068 for CT & CC respectively), while, a significant association between the C (m2) allele and COPD was found (P=0.04). IL-13 -1055 T allele and CYP1A1 MspI C (m2) allele were found to be significantly associated with more severe cases of COPD when compared to the less severe ones (P= 0.03 & 0.02, respectively). Conclusions: IL-13 -1055 C/T polymorphism is associated with COPD, and the presence of IL-13 T allele and CYP1A1 MspI C (m2) allele are risk factors for developing more severe COPD.