Objective. To investigate the impact of tumor necrosis factor inhibitor (TNFi) treatment and inflammation control on radiographic progression in early ankylosing spondylitis (AS) over 4 years.Methods. We included a total of 215 patients with early AS (symptom duration <10 years) treated with TNFi (the TNFi group; n = 135) or with nonsteroidal antiinflammatory drugs (NSAIDs) (the control group; n = 80). Two blinded readers assessed radiographic progression using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Inflammation control was inferred from C-reactive protein (CRP) levels time-averaged between 2 radiologic assessments. Linear mixed modeling was used to estimate mSASSS changes over radiographic intervals as well as the impact of clinical factors on outcomes.Results. The TNFi group had longer disease duration, a higher baseline CRP level, and a higher Bath Ankylosing Spondylitis Disease Activity Index than did controls. The time-averaged CRP level over radiographic intervals was lower with TNFi treatment than with NSAID treatment (mean ± SD 0.27 ± 0.30 mg/dl versus 0.61 ± 0.68 mg/dl; P < 0.001). Overall, mean ± SD mSASSS change over the 2-year interval was 1.30 ± 2.97 units. In the multivariable model adjusted for age, smoking status, baseline CRP level, and the presence of syndesmophytes at baseline, the TNFi group showed less mSASSS change over the 2-year interval (β = −0.90 [95% confidence interval {95% CI} −1.51, −0.29]). However, when a time-averaged CRP level was additionally included, it significantly influenced the mSASSS change (β = 1.02 [95% CI 0.32, 1.71]), decreasing the estimated group difference (β = −0.52 [95% CI −1.17, 0.14]). NSAID indices of both groups were not associated with either time-averaged CRP levels or mSASSS changes.Conclusion. Effective suppression of inflammation by TNFi treatment decreases radiographic progression in early AS.