OBJECTIVE: To assess the effect of reproductive factors, especially hormone replacement therapy (HRT) and its interaction with HLA-DRB1 *01 and/or *04 alleles on the diagnosis of rheumatoid arthritis (RA) and the presence of anti-cyclic citrullinated peptide (CCP) antibodies in women included in the ESPOIR cohort (early arthritis cohort). METHODS: 568 patients were included in the analyses, which were performed using logistic regression. RESULTS: HRT reduced the risk of RA due to the HLA-DRB1 *01 and/or *04 alleles from OR 1.88 (95% CI 1.32 to 2.68, p<0.000) for HLA-DRB1 *01 and/or *04 alleles alone to OR 1.07 (95% CI 0.51 to 2.26, p=0.85) in women with HLA-DRB1 *01 and/or *04 alleles who received HRT. One explanation might be the protective effect of HRT on the presence of anti-CCP antibodies (OR 0.43, 95% CI 0.24 to 0.77, p<0.006). Other reproductive factors such as the number of pregnancies, menopause and age at menopause, age at menarche and a history of pregnancy with poor outcome were not associated with the diagnosis of RA and the presence of anti-CCP antibodies. CONCLUSION: HRT may reduce the risk of RA due to HLA-DRB1 *01 and/or *04 alleles by protecting against the production of anti-CCP antibodies.