BACKGROUND Pemphigus vulgaris (PV) is known to be strongly associated with particular alleles of the human leukocyte antigen (HLA)-DRB1* loci. However, to date, the association of HLA with pemphigus has not been studied in a Syrian population. OBJECTIVE We aimed to study HLA-DRB1* loci variation in Syrian PV patients. METHODS We used a sequence-specific primer polymerase chain reaction method to define the allele type of the DRB1* loci in 91 patients with PV and 270 healthy control subjects. RESULTS We noticed an increased frequency of HLA-DRB1*04 and DRB1*14 alleles in patients with PV compared with healthy control subjects (67.0% vs. 26.3%; odds ratio [OR] = 5.7, corrected P < 0.0001 for DRB1*04; 54.9% vs. 11.0%; OR = 9.5, corrected P < 0.0001 for DRB1*14). Among DRB1*04-positive PV patients, the DRB1*402 subtype was markedly increased compared with DRB1*04-positive healthy controls (84.3% vs. 26.7%; corrected P = 0.002), whereas the DRB1*0403 variant was represented more commonly in DRB1*04-positive healthy individuals than in DRB1*04-positive PV patients (45.0% vs. 1.6%; corrected P < 0.0001). In addition, the frequency of DRB1*11 was significantly decreased in PV patients compared with healthy controls (19.7% vs. 50.4%; OR = 0.25, corrected P < 0.0001). CONCLUSIONS The occurrence of PV is positively associated with HLA-DRB1*14 and HLA-DRB1*0402 but negatively associated with HLA-DRB1*11 in the Syrian population.