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Abstract: Introduction: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory and multifactorial disease. Genetic predisposition seems to play an important role. The aim of this study is to explore the relationship between human leukocyte antigen (HLA)‐DRB1 alleles and susceptibility, clinical and biological features of RA in an Algerian patient population. Methods: Using polymerase chain reaction – sequence specific primers (SSP), 134 RA patients and 132 healthy controls were genotyped for HLA‐DRB1 and HLA‐DRB1*04 subtypes. Results: HLA‐DRB1*04 was found to have increased frequency in the RA group compared to controls (P < 0.001, OR = 3.14), and was associated with anti‐citrullinated protein antibodies positivity (ACPA) (P = 0.01, OR = 2.35). In contrast, HLA‐DRB1*07 was found to have a decreased frequency in patients compared to controls (P = 0.003, OR = 0.44) and significant decrease was observed in patients with the rheumatoid factor (RF) positivity subgroup (P = 0.009, OR = 0.29). HLA‐DRB1*04:05 was associated with RA (P = 0.005, OR = 3.41), whereas, HLA‐DRB1*04:02 showed a protective effect against RA (P = 0.003, OR = 0.20). Conclusions: HLA‐DRB1*04 was associated with increased risk for RA and ACPA positivity, while HLA‐DRB1*07 was associated with reduced risk for RA and RF synthesis in Algerian patients. [ABSTRACT FROM AUTHOR]