<p>Fragile X-related protein 1 (FXR1) is an m⁶A-binding protein that plays a critical role in cancer development and progression. It has unclear associations between its genetic variants and breast cancer (BC) susceptibility. This study explored correlations of FXR1 single nucleotide polymorphisms (SNPs) with BC susceptibility. A frequency matching case-control study included 802 histologically confirmed BC cases and 802 age-matched controls (± 2 years) of Han-Chinese ethnicity. Four FXR1 SNPs were selected using bioinformatics. Associations with BC risk and reproductive factor interactions were assessed using conditional logistic regression. FXR1 expression was evaluated by quantitative real-time PCR (qRT-PCR), with RNA structural and miRNA-binding changes predicting using RNAfold and miRNASNP. The m⁶A-related target genes were identified by QTLbase and RMBase. Tissue expression analyzed via GEPIA. The FXR1 rs2601 A &gt; G variant was significantly associated with reduced BC risk, confirmed by stratification. For rs2601, the said polymorphism exhibited association with the reduced incidence with BC in specific subgroups of studied cohort when comparison was conducted between homozygous wild type AA and AG + GG genotypes. Haplotype analysis revealed the haplotype A_rs1058382A_rs1805607A_rs2601T_rs6799476 and T_rs1058382A_rs1805607G_rs2601T_rs6799476 is probably protective to the incidence of BC in this population. Additionally, a significant additive interaction was observed between rs2601 and age at menarche. qRT-PCR showed genotype-dependent FXR1 expression. Integrative analysis identified 10 candidate associated genes, among which CCDC39 was downregulated in BC tissues(<i>P</i> &lt; 0.01). The FXR1 rs2601 A &gt; G is probably protective to BC among Han Chinese women and it has an interaction with reproductive factors. This could provide theoretical basis for BC screening and prevention.</p>