Objective.To investigate sex differences in response to anti-tumor necrosis factor-α (TNF-α) therapy over time in early versus established rheumatoid arthritis (RA).Methods.Patients with RA who initiated anti-TNF therapy between January 2003 and June 2008 in Denmark were selected from the DANBIO Registry. Sex differences in baseline disease features were examined using chi-square, Mann-Whitney U tests, and t tests. Using a generalized estimating equations (GEE) model for repeated measures, we examined European League Against Rheumatism (EULAR) responses in men and women over 48 months of followup, adjusting for baseline values of age, 28-joint Disease Activity Score (DAS28), disease duration, and anti-TNF, methotrexate, and prednisolone use.Results.At initiation of anti-TNF therapy (baseline), 328 women and 148 men had early RA (≤ 2 yrs), and 1245 women and 408 men had established RA (> 2 yrs). In both early and established RA, men and women had active disease with similar DAS28 scores (mean ± SD 5.2 ± 1.1), physician global scores, swollen joint counts, and radiographic changes. In early RA, men were significantly more likely to achieve a EULAR good/moderate response over 48 months compared to women (GEE; p = 0.003), and a significant interaction between sex and followup time (GEE; p < 0.0005) suggested that men achieved this response sooner than women.Conclusion.Better responses to anti-TNF therapy among men compared to women in early but not established RA suggest that disease duration at initiation of therapy may be an important factor to consider when investigating sex differences in treatment responses.