The etiology of Systemic lupus erythematosus (SLE) seems to be multifactorial including environmental as well as genetic factors. Major histocompatibility complex (MHC) genes especially HLA-DRB1 and HLA-DQB1 are strongly implicated in susceptibility to SLE. Moreover ethnicity has been found to have a significant role in both disease susceptibility and disease expression. This study was carried out to determine HLA-DRB1 allele association with SLE susceptibility and disease presentation in Egyptian children with juvenile onset SLE. HLA-DRB1 allele typing was done using polymerase chain reaction-sequence-specific oligonucleotide probe for 65 juvenile Egyptian SLE patients and 150 healthy controls. p-values were corrected for the number of the alleles tested (Pc). HLA-DRB1*15 g allele was significantly increased in SLE children versus controls (OR = 4.76; 95% CI = 1.83-12.4; p = 0.001 and Pc = 0.012). No HLA-DRB1 allele was found to be statistically significant associated with musculoskeletal, cutaneous, hematologic, cardiac or neuropsychiatric manifestations in SLE patients (p > 0.05). Moreover no statistically significant association was found between HLA-DRB1 alleles and clinical presentation or histologic classes of lupus nephritis. The current work suggests that HLA-DRB1*15g allele may be a susceptibility allele in Egyptian children with SLE but is not related to clinical presentation of SLE.