Objective: To assess change of disease activity and the functional status of patients with ankylosing spondylitis (AS) during treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), synthetic disease-modifying antirheumatic drugs (DMARDs), and tumor necrosis factor-α (TNF-α) inhibitors in a Bulgarian population. Subjects and methods. Sixty-six patients with AS were examined at baseline and after 6 months 25 (37.9%) from them received NSAIDs, 14 (21.2%) – synthetic DMARDs (sulfasalazine and methotrexate), and 27 (40.9%) – TNF-α inhibitors (adalimumab and etanarcept). The disease activity was assessed by BASDAI, ASDAS-CRP, ASDAS-ESR, ESR, and C-reactive protein (CRP), as well as by physician's and patient's assessments. Functional failure was deter- mined by BASFI, DFI, HAQ-S, and BASMI. ASAS improvement criteria and ASDAS changes (clinical improvement Δ ≥1.1 units and considerable improvement Δ ≥2.0 units) were used to assess response to therapy. ASAS criteria were employed to confirm remission. Results. After 12 months of NSAID therapy, there was a statistically significant decrease of CRP level (p < 0.05) and an increase of DFI (p < 0.05). ASAS and ASDAS-ESR 20% improvement Δ ≥1.1 was noted in one case; ASAS 5/6 in 8% of cases. There was a 40% improvement and partial remission in ASAS, as well as in ASDAS Δ ≥2.0 in none patient. Treatment with synthetic DMARDs showed no statistically significant changes in activity and functional sta- tus and ASAS 20% response in 14.3% of the patients. A 40% response in ASAS, ASAS5/6, ASDAS Δ ≥1.1 and ASDAS-ERS Δ ≥2.0 was seen in 7.1%. No partial remission was observed. TNF-α inhibitor treatment provided sig- nificant improvement of all activity and function indicators (Δ ≤ 0.001). There was ASAS 20% response in 63% of cases, 40% response in 48.1%, ASAS5/6 in 59.3%, partial remission in 33.3%, ASDAS-CRP Δ ≥1.1 in 66.7%, ASDAS-CRP 2.0 in 48.1%, ASDAS-ESR Δ≥1.1 in 63% and ASDAS-ESR Δ≥2.0 in 37% of cases. Comparison of therapy response showed that the use of TNF-α inhibitors provided better results (p