Apoptosis is a major protective mechanism against cancer. The tumor suppressor protein p53 is the central protein in the apoptotic pathway and was shown to harbor mutations in a considerable fraction of breast cancer tumors. The NQO1 was shown to act as a p53 stabilizer and was suggested to play an important role in the protection against carcinogenic catechol estrogens. Functional polymorphisms in TP53 and NQO1 were investigated in relation to breast cancer susceptibility in several studies, primarily involving Asian and Caucasian populations. The aim of the present study was to investigate TP53 and NQO1 polymorphisms and their combined effects with respect to breast cancer susceptibility in a Syrian study cohort. The study cohort consisted of 122 cases and 139 controls. The tetra-primer ARMS-PCR method was used to genotype three TP53 polymorphisms; namely, exon 4 G>C Arg72Pro, IVS3 16 bp Del/Ins, and MspI IVS6+62A>G, and NQO1 C609T (Pro187Ser) polymorphism. Association was tested under six genetic models. We found a significant association for the heterozygous Arg/Pro genotype when combined with heterozygosity for IVS3 16 bp Del/Ins and MspI IVS6+62A>G (OR = 2.05 (1.22-3.47), P = 0.006). No significant association was found for NQO1 C609T or its combinations with TP53 polymorphisms. Our results support an association for TP53 polymorphisms with breast cancer susceptibility in the Syrian population.