Objective: To investigate whether the impact of long-term treatment (> 3 years) with TNF inhibitors (TNFi) on radiographic progression in AS is associated with the level of acute phase reactants during therapy. Methods: One hundred and one consecutive AS patients under TNFi [65 men; age: 41.6 ± 11 years (mean ± SD), with symptom duration: 17 ± 10 years] were included in this retrospective study. Lateral X-rays of cervical and lumbar spine, obtained before TNFi initiation, were compared to those obtained after a period of 7 ± 2.5 (range: 3–15) years. The levels of CRP and ESR were evaluated every 6 months. The modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) assessed the radiographic damage. New syndesmophyte formation or ΔmSASSS-score/year ≥ 1 unit/year was defined as radiographic progression. Results: Forty-seven patients (46.5%) showed radiographic progression. ΔmSASS-score/year was positively correlated with both, baseline CRP (r = 0.35, P < 0.001) and ESR (r = 0.3, P < 0.01), as well as with time-averaged CRP (r = 0.3, P < 0.01). Furthermore, ΔmSASS-score/year was significantly higher (P < 0.0001) in patients with syndesmophytes at baseline [0.9 (0.4–1.8), median (IQR)] compared to those without [0 (0–0.4)]. In the multivariate logistic regression analysis, independent risk factors for spinal radiographic progression during TNFi treatment were the presence of syndesmophytes at baseline (OR: 14.7, 95%CI:4.9–44) and the time-averaged CRP > 5 mg/L (OR:7.6, 95%CI: 2.5–23). No gender differences were observed. Conclusion: In AS patients with long standing disease, radiographic progression during TNFi treatment is significantly associated with higher levels of time-averaged CRP.