Background: Previous studies about the correlation of genetic polymorphisms in the multigene family of cyto- chrome P450 (CYPs), the effect of tobacco smoking, and the risk of developing cancer have been well in- vestigated in different populations, but not in Iraq. Furthermore, the studies of malignance occurrence re- lationship with cigarette tobacco smoking revealed the presence of strong association, however, little is known about the risk of Waterpipe (WP) tobacco smoking. Thus, determination two important genetic polymorphisms in CYP1A1, a main member of CYPs, among Iraqi men was our first aim. This is the first study that highlights the correlation of CYP1A1 polymorphisms with the risk of lung cancer in Iraq. The second aim was to evaluate the combined association of WP tobacco smoking and CYP1A1-Ile462Val and -MspI polymorphisms in lung cancer risk. Methods: This study included 123 lung cancer patients and 129 controls. To determine the variant genotypes, the techniques of Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and DNA sequencing were carried out. Results: The data revealed the possible associations of variant (G) allele of CYP1A1-Ile462Val (OR = 1.6; 95% CI = 1.1–2.4; P = 0.01) and variant (C) allele of CYP1A1-MspI (OR = 1.9; 95% CI = 1.3–2.7; P < 0.01) with the risk of lung cancer. The variant genotypes of CYP1A1 polymorphisms were significantly correlated in the case of squamous cell carcinoma and synergistically associated in the case of combined effect with WP tobacco smoking (ORIleVal = 2.0; 95% CI = 1.0–4.1; P = 0.04, and ORMspI = 2.6; 95% CI = 1.3–5.5; P ≤ 0.01). Conclusion: The results suggest that WP tobacco smoking and genetic polymorphisms in CYP1A1 are most likely important risk factors for lung cancer in the Iraqi population.