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Background: The era of biological therapy has revolutionized in the management of autoimmune rheumatic diseases. There have been conflicting results about the incidence of infections related to these drugs. The purpose of this study was to compare the spectrum and severity of infection between patients on biological disease-modifying antirheumatic drugs (bDMARDs) versus conventional disease-modifying antirheumatic drugs (cDMARDs). Materials and Methods: This hospital-based prospective observational study was conducted in a tertiary care hospital, and a total 200 patients were enrolled in this study. Patients on either bDMARDs or cDMARDs for at least six weeks presenting with evidence of infection were included. Patients with known immunodeficiency states, multiple comorbidities, and patients on prednisolone >7.5 mg were excluded. Data was expressed as percentage and mean ± SD. Kolmogorov-Smirnov analysis was performed for checking linearity of the data, and analysis of variance (ANOVA) followed by Tukey's HSD test were used to test the significance of difference between more than two parameters in parametric data. Results: Rheumatoid arthritis in 58 patients (29%) were the commonest ones presenting with infections, followed by systemic lupus erythematosus in 37 patients (18.5%). 135 patients (67.5%) were on cDMARDs and 65 patients (32.5%) on bDMARDs. Respiratory tract infection in 47 (34.8%) patients was found to be the commonest infection due to cDMARDs. Incidence of infection was higher with biologics, and types of infection in patients receiving infliximab and etanercept were significantly different from that of cDMARDs. Patients receiving etanercept had higher risk of infections and re-infections, but they were milder compared to cDMARDs. A significantly higher frequency of re-infection was found in patients who had not received vaccination. Conclusion: This study emphasizes that TNF-α inhibitors are significantly associated with higher risk of infections. Patients on etanercept have significantly higher but milder infections as compared to cDMARDs. Vaccination plays a pivotal role in prevention of re-infections. [ABSTRACT FROM AUTHOR]