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Objective The primary objective was to assess sex differences in long-term functional deterioration and permanent work disability in spondyloarthritis (SpA), and the secondary aim to evaluate whether systemic inflammation mediates the association between biologic disease-modifying antirheumatic drugs (bDMARDs) exposure and functional change in a sex-dependent manner.Methods A longitudinal observational study was conducted in 411 patients with SpA from the Spanish REGISPONSER registry (baseline 2004–2007), who were reassessed 17 years later in REGISPON-3 (2021–2024). Outcomes were Bath Ankylosing Spondylitis Functional Index (BASFI) at follow-up, ΔBASFI and permanent work disability. Sex-stratified logistic and multivariable linear regression models were used. Moderated mediation analysis evaluated C reactive protein (CRP) as a mediator of the association between bDMARD exposure and ΔBASFI, with sex as a moderator.Results A total of 271 male patients with SpA (65.9%) and 140 female patients with SpA (34.1%) were included. At follow-up, female patients showed significantly worse functional status and greater functional deterioration (ΔBASFI 1.47±2.81 vs 0.38±2.57, p<0.001), whereas permanent disability rates were similar (27.1% vs 32.1%, p=0.31). Higher Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Radiology Index (BASRI)-total were independently associated with disability in both sexes. Baseline BASFI and BASDAI predicted ΔBASFI in both sexes; additional predictors in male patients included BASRI-total and occiput-to-wall distance, whereas BASRI-column was relevant in female patients. The indirect effect of bDMARD exposure on ΔBASFI through CRP was significant in male patients but not in female patients with a significant sex interaction.Conclusion Female patients experienced greater long-term functional deterioration despite similar work disability rates at follow-up. The relationship between systemic inflammation and long-term functional outcomes may differ by sex.