Abstract: HLA‐DRB1 shared epitope (SE) alleles are important genetic contributors for the risk of developing anti‐citrullinated protein antibodies (ACPA)‐positive rheumatoid arthritis (RA), particularly in Caucasians. We aimed to analyze the contribution of HLA‐DRB1 alleles and single nucleotide polymorphisms (SNPs) within the major histocompatibility complex (MHC) region to the susceptibility to develop ACPA‐positive RA in a Latin American (LA) population with admixed ancestry. A total of 289 ACPA‐positive RA patients and 510 controls were enrolled in this study. The presence of HLA‐DRB1*04:01, *09:01 and *10:01 was increased in ACPA‐positive RA patients compared with healthy controls (p < 0.0001, p < 0.001 and p < 0.01, respectively), whereas DRB1*07:01 and *08:02 was associated with a decreased risk of ACPA‐positive RA (p < 0.001 and p < 0.01, respectively). These results showed a strong correlation with estimates from studies in Asians but not in Caucasian populations. The present study describes the protective effects of the HLA‐DRB1*07:01 and *08:02 alleles in ACPA‐positive RA patients in a LA population for the first time. Identifying relationships between HLA‐DRB1 alleles and RA is important for identifying disease associations in different ethnic groups in order to reach a better understanding of RA worldwide.