The aim of this study was to determine the Human Leukocyte Antigen (HLA) class II (DRB1andDQB1) alleles and haplotype frequency in Rheumatoid Arthritis(RA) in the Sudanese population. The frequency ofHLA-DRB1and -DQB1alleles andDRB1-DQB1haplotypes were determined in 122 RA patients and 100 controls. HLA alleles were genotyped by the polymerase chain reaction-sequence specific primers (PCR-SSP) method. In RA patients,HLA-DRB1*04 and *10alleles were high in frequency (9.6% vs 14.2%,P= 0.038 andP= 0.042, respectively), and dependently on anti-citrullinated protein antibodies (ACPAs) seropositivity (P= 0.044 andP= 0.027, respectively). In contrast, the frequency of theHLA-DRB1*07allele was significantly low in patients than in controls (11.7% vs 5.0%,P= 0.010). Moreover, theHLA-DQB1*03allele was strongly associated with RA risk (42.2%,P= 2.2x10-8), whereas,HLA-DQB1*02and*06showed protective effects against RA (23.1% and 42.2%,P= 0.024 andP= 2.2x10-6, respectively). Five different HLA haplotypes,DRB1*03-DQB1*03(P= 0.00003),DRB1*04-DQB1*03(P= 0.00014), DRB1*08-DQB1*03(P= 0.027), DRB1*13-DQB1*02(P= 0.004), andDRB1*13-DQB1*03(P= 3.79x10-8) were significantly associated with RA risk, while 3 protective haplotypes, DRB1*03-DQB1*02(Pc= 0.008),DRB1*07-DQB1*02(Pc= 0.004), and DRB1*13-DQB1*06(Pc= 0.02) were identified. This is the first study determining the association between HLA class II alleles and haplotypes and RA risk in our population.