Background <p>The causal connection between circulating inflammatory biomarkers and breast cancer susceptibility has not been definitively established.</p> Methods <p>We conducted a comprehensive Mendelian randomization investigation to examine potential causal links between inflammatory mediators and breast cancer development. Utilizing genome-wide association study data, we analyzed 91 circulating inflammatory markers in relation to breast cancer occurrence through a two-sample Mendelian randomization approach to determine causal relationships.</p> Results <p>Our analysis revealed that 13 inflammatory biomarkers demonstrated potential causal associations with breast cancer development (<i>P</i> &lt; 0.05). However, after implementing false discovery rate (FDR) adjustment for multiple testing, only two inflammatory mediators maintained statistical significance (PFDR &lt; 0.05): Leukemia inhibitory factor receptor (LIFR) concentrations and C-X-C motif chemokine 5 (CXCL5) concentrations, both showing inverse causal relationships with breast cancer risk.</p> Conclusion <p>This investigation demonstrates that elevated LIFR and CXCL5 concentrations exhibit protective effects against breast cancer development, indicating an inverse causal relationship between these inflammatory markers and breast cancer susceptibility. These findings suggest that CXCL5 and LIFR may serve as protective biomarkers in breast cancer prevention.</p>