BACKGROUND The association between triglyceride-glucose (TyG)-related indices and breast cancer risk is not fully understood. This study aimed to investigate the role of TyG-related indices in predicting breast cancer risk. METHODS We analyzed data from 220,396 female participants in the UK Biobank, with a median follow-up of 13.63 years. TyG-related indices including TyG, TyG-body mass index (TyG-BMI), TyG-waist circumference (TyG-WC), TyG-waist to height ratio (TyG-WHtR), TyG-waist to hip ratio (TyG-WHR). Cox proportional hazards models were used to evaluate the association between TyG-related indices and breast cancer risk. Mediation analysis was performed to assess the role of white blood cell (WBC) and C-reactive protein (CRP) in this association. Interaction analysis was conducted to assess if age, menopausal status, and breast cancer screening modified the association between TyG-related indices and breast cancer risk. RESULTS The highest quartiles of TyG, TyG-BMI, TyG-WC, TyG-WHtR, and TyG-WHR were significantly associated with increased breast cancer risk, with hazard ratios (95% CI) of 1.10 (1.04-1.17), 1.28 (1.20-1.35), 1.30 (1.22-1.38), 1.23 (1.16-1.31), and 1.17 (1.10-1.24), respectively. Interaction analysis revealed stronger associations in postmenopausal women, those aged ≥ 60, and individuals who had not undergone breast cancer screening (P for interaction < 0.05). Mediation analysis showed that CRP contributed a larger proportion of the mediation effect than WBC, with CRP mediating 26.8%-54.7% and WBC mediating 14.3%-40.4%. CONCLUSIONS TyG-related indices were significantly associated with increased breast cancer risk, highlighting their potential as biomarkers for risk assessment and prevention strategies.