Human leukocyte antigen (HLA)-G is a non-classical HLA class I molecule that exerts a generalized immunosuppressive action. A deficit in membrane bound and soluble HLA-G levels seems to cause a defective control on immune responses and trigger off several autoimmune diseases. As psoriasis is considered an autoimmune disease, lower levels of soluble HLA-G (sHLA-G) might be expected in psoriatic patients than in healthy controls. The aims of this descriptive study were: (1) to evaluate whether sHLA-G levels are different in psoriatic patients compared to controls; (2) to compare sHLA-G levels between groups of patients treated with different therapies; (3) to evaluate whether any differences found in HLA-G expression could be related to a genetic control. Peripheral blood samples were investigated for sHLA-G and IL-10 levels and for HLA-G 14 bp polymorphism in 65 patients with moderate-to-severe plaque psoriasis treated with systemic drugs or with topical or physical treatments and in controls. Significantly lower plasma levels of both sHLA-G and IL-10 were found in psoriatic group compared to controls and in local treated patients in comparison with systemic treated patients. These findings could indicate that low sHLA-G levels may contribute to susceptibility to psoriasis. Absence of differences in HLA-G 14 bp allele and genotype frequencies between psoriatic patients and controls and between patients following different treatments seems to exclude genetic bases of sHLA-G levels. It could be speculated that therapeutics antagonizing systemic T helper 1 activation may induce sHLA-G secretion via an IL-10-dependent pathway.