Abstract Objectives Fat lesions (FLs) on MRI T1 sequences are considered to be early indicators of structural spinal progression in axial spondyloarthritis (axSpA) patients. In this post-hoc analysis from RAPID-axSpA, we assess whether tumour necrosis factor inhibitor (TNFi) treatment over 4 years impacts FLs in spinal vertebral edges (VEs) of patients with axSpA. Methods In RAPID-axSpA (NCT01087762), a 4-year, phase 3 randomized trial, participants were randomized to certolizumab pegol (CZP; 400 mg loading dose at Weeks 0/2/4 then 200/400 mg every 2/4 weeks) or placebo (PBO) at baseline; PBO-randomized participants switched to CZP at Week 16/24 (denoted PBO-randomized/CZP). Spinal MRI scans were taken at Weeks 0, 12, 48, 96 and 204. Changes in proportions of VEs with FLs are reported as odds ratios (ORs) between time points. Results Overall, 136 participants (CZP: 89, PBO-randomized/CZP: 47) had a baseline and ≥1 post-baseline MRI. The OR (95% confidence interval) vs baseline of FLs was higher in PBO-randomized/CZP vs CZP-randomized participants at Weeks 48 [3.35 (2.16–5.19) vs 1.45 (1.07–1.97)], 96 [2.62 (1.77–3.88) vs 1.84 (1.36–2.48)] and 204 [2.55 (1.59–4.06) vs 1.71 (1.23–2.37)]. Across 204 weeks, FLs increased more in VEs with baseline inflammation [Week 204 OR: 4.84 (2.56–9.18)] than those without [OR: 1.15 (0.78–1.71)]. VEs in which inflammation was resolved by Week 12 had lower FL prevalence at Weeks 48, 96 and 204 compared with VEs with unresolved inflammation. Conclusions Early and sustained suppression of inflammation mitigates the risk of long-term FL development in the spine in study participants with axSpA evaluated over 4 years. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT01087762.