Glutathione-S-transferases (GSTs) play a role in the detoxification of environmental chemicals and mutagens, such as those inhaled during tobacco smoking. There have been conflicting reports concerning GST polymorphisms as risk factors in the development of lung cancer. No studies focused on Arab populations exposed to Waterpipe (WP) tobacco smoke have been undertaken. Here Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and gene sequenc- ing were applied to analyze allelic variations in GSTP1-rs1695 and -rs1138272 amongst 123 lung cancer patients and 129 controls. The data suggest that WP smoking raised the risk of lung cancer more than three-fold (OR 3.6; 95% CI 2.1–6.0; p < 0.0001). However, there was no significant association between individual GSTP1 polymorphisms and the risk of lung cancer. In contrast, analysis of the rs1695 and rs1138272 combination suggested that the risk of lung cancer was raised more than two-fold for carriers of the GSTP1-rs1695 (G) allele (OR 2.5; 95% CI 1.0–6.4; p < 0.05), however, the presence of the GSTP1-rs1138272 (T) allele, in addition to GSTP1-rs1695, did not significantly change the risk ratio (OR2.8; 95% CI 1.4–5.7; p < 0.004). WP tobacco smokers who carried the GSTP1-rs1695, but not GSTP1-rs1138272, allele were similarly susceptible to lung cancer (OR 2.4; 95% CI 1.1–5.3; p < 0.03). Hence, the results suggest that smoking WP tobacco and carrying GSTP1-rs1695 polymorphisms are risk factors for lung cancer in Arab Iraqi males.