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Background Glucocorticoids could theoretically decrease breast cancer risk through their anti-inflammatory effects or increase risk through immunosuppression. However, epidemiological evidence is limited regarding the associations between glucocorticoid use and breast cancer risk. Methods We investigated the association between systemic glucocorticoid use and breast cancer incidence in the E3N cohort, which includes 98,995 women with information on various characteristics collected from repeated questionnaires complemented with drug reimbursement data available from 2004. Women with at least two reimbursements of systemic glucocorticoids in any previous 3-month period since January 1, 2004, were defined as exposed. We considered exposure as a time-varying parameter, and we used multivariable Cox regression models to estimate hazard ratios (HRs) of breast cancer. We performed a competing risk analysis using a cause-specific hazard approach to study the heterogeneity by tumour subtype/stage/grade. Results Among 62,512 postmenopausal women (median age at inclusion of 63 years old), 2864 developed breast cancer during a median follow-up of 9 years (between years 2004 and 2014). Compared with non-exposure, glucocorticoid exposure was not associated with overall breast cancer risk [HR = 0.94 (0.85–1.05)]; however, it was associated with a higher risk of in situ breast cancer and a lower risk of invasive breast cancer [HRinsitu = 1.34 (1.01–1.78); HRinvasive = 0.86 (0.76–0.97); Phomogeneity = 0.01]. Regarding the risk of invasive breast cancer, glucocorticoid exposure was inversely associated with oestrogen receptor (ER)-positive breast cancer [HRER+ = 0.82 (0.72–0.94); HRER− = 1.21 (0.88–1.66); Phomogeneity = 0.03]; it was also inversely associated with the risk of stage 1 or stage 2 tumours but positively associated with the risk of stage 3/4 breast cancers [HRstage1 = 0.87 (0.75–1.01); HRstage2 = 0.67 (0.52–0.86); HRstage3/4 = 1.49 (1.02–2.20); Phomogeneity = 0.01]. Conclusion This study suggests that the association between systemic glucocorticoid use and breast cancer risk may differ by tumour subtype and stage. Supplementary Information The online version contains supplementary material available at 10.1186/s12916-021-02004-6.