Background Tumor necrosis factor inhibitors (TNFi) have emerged as an efficient therapeutic modality for rheumatoid arthritis (RA). A ratio of patients does not give a response despite therapy. It remains a challenge to predict which patients will respond. Our study aims to investigate early predictors of primary TNFi failure in RA patients. Patients were categorized into two groups based on TNFi therapy (responder/non-responder) and then compared to detect the most significant predictors of treatment failure.Results This study included 87 RA patients treated with TNFi for the first time after conventional disease-modifying anti-rheumatic drugs (DMARDs) failed. This study showed that compared to those with successful treatment, patients with overall primary failure were significantly higher in older age, females, smokers, obese, younger age at the onset of the disease, or those with deformity. In addition, the drug failure was significantly related to erythrocyte sedimentation rate (ESR) (100 vs 68 mm/h), C-reactive protein (CRP) (48 vs 12 mg/dl), rheumatoid factor (RF) positivity (29% vs 16%), anti-cyclic citrullinated peptide (anti-CCP) positivity (39% vs 23%), and non-methotrexate (MTX) concomitant use (33% vs 40%).Conclusion The increased age, being a smoker, earlier age at onset, presence of a deformity, and positive anti-CCP at baseline were predictors of overall failure. At the same time, concomitant MTX intake increased the success rate by 9.6%. center dot The increased age, being a smoker, earlier age of disease onset, and the presence of a deformity were predictors of overall TNFi primary failure.center dot The overall primary failure of TNFi treatment was significantly related to ESR, CRP, RF positivity, anti-CCP positivity.center dot The regression analysis showed that these combined factors predict 70.1% of the TNFi failure rate.center dot Concomitant MTX intake increased the success rate by 9.6%.