We investigated the distribution of HLA-DRB1 alleles in a sample of the Chinese Shantou population, and explored the relationship between HLA-DRB1 alleles and the susceptibility and clinical features of rheumatoid arthritis (RA). We studied 117 consecutive patients with RA and control groups, including 38 cases of systemic lupus erythematosus and 100 healthy individuals. HLA-DRB1 genotyping was performed using PCR with sequence-specific primers. HLA-DRB1*04 subtypes were detected using spot hybridization of PCR products with sequence-specific oligonucleotide probes. We compared the frequency of HLA-DRB1 alleles in healthy control patients with that in patients with RA. Patients with RA were evaluated for sex, age at disease onset, disease duration, extra-articular involvement, presence of autoantibodies, global functional status, and radiographic damage. The frequency of HLA-DRB1*04 was found to be significantly higher in RA patients than in healthy individuals (49.6% vs 18.0%, odds ratio = 4.478, P < 0.001). HLA-DRB1*0405 was the most prominently associated subtype in RA patients (62.1% vs 27.8%, odds ratio = 4.255, P = 0.011). Compared with the HLA-DRB1*04-negative RA group, the mean duration of RA in the HLA-DRB1*04-positive RA group was longer, and the mean age at disease onset was lower. A 2-9 year follow-up study was performed, and the risk factors associated with the radiographic progression of RA were determined. Logistic regression analysis revealed that only HLA-DRB1*04 alleles were significantly associated with the radiographic progression of RA (B = 2.652, P = 0.018, Exp(B) = 14.182). Our observations indicated that the HLA-DRB1*04 alleles, especially the subtype HLA-DRB1*0405, were significantly associated with RA susceptibility in the Chinese Shantou population. The HLA-DRB1*04 alleles may be associated with the severity of RA.