Objective: the aim of the study was to investigate the relationship between Systemic Sclerosis (SSc) and HLA antigens, and to correlate these antigens with the clinical manifestations of the disease. Materials and methods: 55 patients were stratified according a) to the cutaneous involvement b) to the positivity of Scl- 70 and anticentromere antibody and c) to the internal organ involvement, in particular we used HRCT to demonstrate lung fibrosis, echocardiography for the diagnosis of pulmonary hypertension, blood creatinine, urinalysis and arterial hypertension to demonstrate renal failure, and esophagus double-countrast barium swallow for the diagnosis of esophagopathy. The control group consisting of 2000 healthy Caucasian subjects was recruited from the same population. Results: the frequency of the antigens A23 (p=0.003, RR=3.69), B18 (p<0.0001, RR=3.57), and DR11 (p<0.0001, RR=6.18) was statistically increased in the patients population compared with the healthy controls. Although there is no any significant correlation between HLA antigens and different clinical subsets of scleroderma, antigens B18 and DR11 could be associated with more severe clinical features. Conclusions: the presence of a significant association between SSc and specific HLA antigens (A23, B18, and DR11) could link the HLA system with SSc.