Given the potential link between genetic risk factors and clinical features of systemic lupus erythematosus (SLE), this study aimed to explore the relationship between human leukocyte antigen (HLA)-DRB1/DQB1 alleles and haplotypes and clinical sub-phenotypes of the disease in a group of Iranian SLE patients. HLA-DRB1 and HLA-DQB1 alleles were determined by PCR-SSP in 127 SLE patients and 153 ethnically-matched healthy controls. The relationships between various clinical manifestations and HLA alleles/haplotypes were analyzed in the patients. We observed the positive associations of DRB1*07 and DRB1*07-DQB1*02 haplotypes with articular and pulmonary involvement (p=0.006 and p<0.001 respectively), DRB1*03 and DQB1*02 alleles, and DRB1*03-DQB1*02 haplotypes with cutaneous (p=0.03, p=0.004 and p=0.02 respectively) and renal involvement, and DRB1*13 as well as DRB1*13-DQB1*06 haplotypes with renal involvement. Conversely, negative associations of DRB1*13 with cutaneous and gastrointestinal disorders (p=0.004 and p=0.02 respectively) and DRB1*01 with renal involvement (p=0.03) were found in our patients. Patients carrying susceptible HLA-DRB1 alleles had a higher risk for expression of cutaneous involvement (p=0.03), anti-coagulant antibody development (p=0.01), and a lower risk for pulmonary disorders compared to patients' negatives for susceptible alleles (p=0.04). Our findings on associations between HLA risk allele (DRB1*03) as well as non-risk alleles with particular clinical manifestations and between the potentially protective allele (DRB1*01) and protection against renal involvement indicate the important role of HLA class II genes in predisposing of specific serological and clinical features of SLE disease which could be implicative for therapeutic applications and better management of SLE patients.