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Background: Assessment of disease activity in axial spondyloarthritis (axSpA) has remained a challenge. This study aims to investigate the role of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) as markers of disease activity in patients with axSpA. Methods: A total of 40 patients with axSpA were included in this study. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)/Bath Ankylosing Spondylitis Functional Index (BASFI), serum TNF-α, and VEGF levels were assessed at baseline and the same parameters were assessed after 24 weeks of therapy with either etanercept or NSAIDs (20 patients in each group). Twenty healthy age- and sex-matched controls were also recruited for the study. Results: Patients with axSpA had higher levels of serum TNF-α (mean 341 pg/ml) and VEGF (mean 791 pg/ml) as compared with healthy controls (mean 72.5 pg/ml, P < 0.001 and mean 269 pg/ml, P < 0.001). There was significant reduction in serum TNF-α and VEGF levels after 24 weeks of treatment with etanercept (mean 161 pg/ml, P < 0.001 and mean 442 pg/ml, P < 0.001, respectively) but not with NSAID (P = 0.29, P = 0.25). Both TNF-α and VEGF had a positive correlation with BASDAI (r = 0.57, P < 0.01 and r = 0.44, P < 0.01) and BASFI (r = 0.61, P < 0.01 and r = 0.33, P = 0.03) at baseline. The levels of TNF-α and VEGF showed no correlation with ESR and CRP (P = 0.48, P = 0.07 and P = 0.21, P = 0.06, respectively) at baseline. There was no correlation between BASDAI and levels of ESR, CRP (P = 0.27 and P = 0.49, respectively). Conclusion: Serum levels of TNF-α and VEGF serve as better markers of disease activity as compared with ESR and CRP in axSpA.