To evaluate the potential for gene–gene interaction effects in sporadic breast cancer (BC) risk, we studied combinations of the fibroblast growth factor receptor 2 (FGFR2) rs1219648 and tumor protein 53 (TP53) rs1042522, rs1625895, and rs17878362 polymorphisms in BC patients (n=388) and healthy persons (n=275). In addition to a single-locus effect manifested by the association of FGFR2 rs1219648 and TP53 rs1042522 polymorphisms with high BC risk, depending on menopause status (0.001<p<0.05), we showed a highly significant cooperation between the examined polymorphisms in FGFR2 and TP53 in the determination of susceptibility to the disease. Indeed, we found that combinations of FGFR2 minor and TP53 major genotypes were associated with a high risk of BC, particularly in the postmenopausal period (0.01<p<0.05). In contrast, combinations of the FGFR2 and TP53 major genotypes had a protective effect against BC, especially in premenopausal women (0.001<p<0.01). Of note, all observations were estrogen receptor (ER) dependent. The significant crosstalk between FGFR2 and TP53 polymorphisms was also confirmed by multifactor dimensionality reduction and ordered combinatorial partitioning approaches (0.001<p<0.05). Taken together, data from the present study demonstrate the age- and ER-specific interplay between TP53 and FGFR2 in BC.