The HDL-associated paraoxonase (PON) activities play a role in decreasing oxidative stress, which is known to contribute to cancer development. The aim of this study was to examine the relation between the PON1 L55M and Q192R polymorphisms and breast cancer (BC) risk in Egyptian females and to analyze their relation to clinicopathological parameters of BC. Both polymorphisms were characterized in 100 BC Egyptian females and 100 healthy women who had no history of any malignancy by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, using DNA from peripheral blood in a case control study. With respect to PON1 L55M, the mutated allele (M) frequency was found in 70.5% in BC patients and in 53.5% in controls; the M allele was significantly associated with an increased risk of BC (adjusted odds ratio (OR(adj)) 2.07, 95% confidence interval (95% CI) 1.37-3.13; P = 0.011). The homozygous mutant genotype (MM) significantly increased the risk of BC (OR(adj) 2.07, 95% CI 1.17-3.64, P = 0.011). However, as regard PON1 Q192R, the R mutated allele frequency was found in 28.5% in BC patients and in 33% in controls, the women who were QR heterozygotes (OR(adj) 0.96, 95% CI 0.55-1.68) or RR homozygotes (OR(adj) 0.64, 95% CI 0.25-1.63), and R allele (OR(adj) 0.81, 95% CI 0.53-1.42) did not show any risk for BC. Both PON1 L55M and Q192R polymorphisms genotype frequencies were not related to patient's age (P = 0.94 and 0.72, respectively). M allele genotypes (LM/MM) carriers showed significant association only with nodal metastases (P = 0.02) but not with other clinicopathologic parameters. However, R allele genotype (QR/RR) carriers showed insignificant correlation with clinicopathological parameters. In conclusion, our results suggest that the M allele of L55M polymorphism could be a suitable marker for BC susceptibility and tumor prognosis in Egyptian women.