This study aimed to compare the efficacy of infliximab and etanercept in rheumatoid arthritis (RA) patients to help clinicians select the most effective treatment options. This was a cross sectional study conducted in Urmia, Iran, from March 21, 2017, to February 20, 2018. Data was collected by checklists from RA patients referred to the Rheumatology Clinic of Urmia Imam Khomeini Hospital who were receiving either infliximab or etanercept. Inclusion criteria were a diagnosis of RA according to the revised 2016 criteria of the American College of Rheumatology (ACR)/European League Against Rheumatism, aged over 18, consent to participate in the study, and poor response to other drugs. Both genders were included. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tender joint count (TJC), swollen joint count (SJC), and disease activity score (DAS) (28 scores) were analyzed before and after treatment. In a total of 44 eligible patients, 13 patients received infliximab and 31 received etanercept. The mean age was 53.92 ± 10.94 and 52.8 ± 64.13 years in the infliximab and etanercept groups, respectively. No significant differences were reported concerning ESR (p value = 0.97) or CRP (p value = 0.96), while a significant decrease in the infliximab group compared to the etanercept group was demonstrated in terms of DAS28 scores (p value = 0.028), global health (GH)1 (p value = 0.005), SJC (p value = 0.008), and TJC (p value = 0.01). This study demonstrated a significant difference between the two groups in the DAS scores 28, SJC, TJC, and GH.