OBJECTIVE Tumor necrosis factor-alpha has a prominent role in the inflammatory process and bone resorption in patients with ankylosing spondylitis (AS). We evaluated the markers of clinical efficacy and bone biochemical changes in Korean patients with AS treated with etanercept therapy. METHODS Serum samples from 26 patients receiving etanercept for refractory AS were obtained at baseline and 12 weeks after treatment. Clinical measures and serum levels of transforming growth factor-Beta (TGF-Beta), matrix metalloproteinase-3 (MMP-3), macrophage-colony stimulating factor (M-CSF), bone-specific alkaline phosphatase (BALP), osteocalcin, C-telopeptide (CTX), receptor activator of nuclear factor-kB ligand (RANKL), and osteoprotegerin (OPG) were measured at each timepoint. RESULTS Significant improvement of the Bath AS Disease Activity Index (BASDAI) and Functional Index (BASFI) was achieved after 12 weeks (p < 0.001). ASsessments in Ankylosing Spondylitis Working Group (ASAS) 20 criteria were achieved by 22 patients (84.6%) after 12 weeks' treatment. ASAS 50 and 70 were achieved by 10 (38.5%) and 7 patients (26.9%). Serum levels of BALP and osteocalcin were significantly increased after 12 weeks of treatment (p < 0.05). Serum levels of CTX were not changed after treatment. Serum levels of TGF-Beta, MMP-3, and M-CSF were significantly decreased after 12 weeks of treatment (p < 0.05). Serum levels of OPG and RANKL were not changed. Change of MMP-3 had a high correlation coefficient with changes of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) upon etanercept treatment (CRP, r = 0.446, p = 0.022; ESR, r = 0.449, p = 0.021). CONCLUSIONS In patients with AS, etanercept therapy may be effective for reducing disease activity and improving bone biochemical markers. MMP-3 may be a useful biomarker for monitoring etanercept therapy.