Background: Rheumatic diseases, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, are chronic inflammatory conditions that significantly impact patients' quality of life. Biologic disease-modifying antirheumatic drugs (bDMARDs) have transformed treatment strategies by specifically targeting immune pathways involved in disease progression. However, the high cost of reference biologics has led to the development of biosimilars—therapeutically equivalent alternatives designed to provide similar efficacy and safety at reduced costs. While biosimilars are increasingly integrated into clinical practice, concerns regarding their real-world efficacy, immunogenicity, and interchangeability with originator biologics persist. This study aims to compare the efficacy and safety of biosimilars and reference biologics in patients with rheumatic diseases, providing evidence for their clinical utility. Objectives: The primary objective of this study is to evaluate the comparative efficacy of biosimilars and reference biologics in the management of rheumatic diseases. Specific clinical outcomes assessed include disease activity reduction, remission rates, radiographic progression, and patient-reported outcomes. Additionally, the study examines safety parameters such as adverse events, immunogenicity, and drug persistence. Methods: A prospective observational study was conducted at a tertiary care center in India, enrolling 100 patients diagnosed with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis. Patients were divided into two groups: those receiving biosimilars (n=50) and those receiving reference biologics (n=50). Clinical efficacy was assessed using the Disease Activity Score in 28 joints (DAS28) for rheumatoid arthritis, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for ankylosing spondylitis, and the Psoriasis Area and Severity Index (PASI) for psoriatic arthritis. Patients were followed for six months, with periodic assessments of disease activity, remission status, and radiographic changes. Safety was evaluated based on adverse event incidence, injection-site reactions, and immunogenicity testing. Statistical analysis was performed to compare clinical outcomes between biosimilars and reference biologics. Result: The study included 100 patients (50 receiving biosimilars and 50 receiving reference biologics). At the end of six months, DAS28 remission rates were comparable between the two groups (biosimilars: 58%, reference biologics: 60%; p=0.79). Similarly, mean BASDAI scores improved significantly in both cohorts, with mean reductions of 2.7 points for biosimilars and 2.9 points for reference biologics (p=0.81). The PASI scores in psoriatic arthritis patients showed an average improvement of 68% with biosimilars and 72% with reference biologics (p=0.75), indicating comparable efficacy. Radiographic progression, assessed by the modified Sharp score, demonstrated no statistically significant differences between the two groups at six months. Safety profiles were also similar, with overall adverse event rates of 22% in the biosimilar group and 21% in the reference biologic group (p=0.88). Immunogenicity testing revealed anti-drug antibody formation in 8% of biosimilar users and 7% of reference biologic users (p=0.90), reinforcing the comparable safety of both treatments. Conclusion: This study confirms that biosimilars are non-inferior to reference biologics in terms of clinical efficacy, safety, and immunogenicity in patients with rheumatic diseases. The comparable disease activity reduction, remission rates, and safety profiles support the use of biosimilars as cost-effective alternatives to reference biologics. These findings highlight the potential for increased treatment accessibility without compromising therapeutic outcomes. Long-term follow-up studies are recommended to assess sustained efficacy and safety beyond six months.