BACKGROUND: Human leukocyte antigen-G (HLA-G), a protein primarily expressed during pregnancy, helps maintain maternal-fetal immune tolerance. Myocardial and/or soluble HLA-G (sHLA-G) expression confers protection against rejection and vasculopathy after heart transplantation. Although the precise mechanisms remain unclear, immunosuppressive therapy has been reported to influence this expression. METHODS: We compared sHLA-G expression in heart transplant recipients receiving two different anti-proliferative agents: mycophenolate mofetil (MMF) and everolimus (RAD). Twelve-hour pharmacokinetic (PK) studies were conducted in patients after cyclosporine (CsA) administration in conjunction with RAD or MMF, during which plasma HLA-G concentrations were measured by enzyme-linked immunoassay (ELISA). RESULTS: Among patients receiving RAD, 78% expressed detectable levels of plasma HLA-G (1,002 +/- 511 ng/ml) compared with 25% of patients receiving MMF (612 +/- 438 ng/ml, p = 0.03). In all sHLA-G(+) patients, expression remained constant, with no significant changes in HLA-G levels throughout the 12-hour PK study period. CsA did not appear to influence sHLA-G expression, as there was no correlation between HLA-G levels and CsA exposure (R(2) = 0.43, p = 0.08). CONCLUSIONS: These preliminary findings suggest a disproportionate expression of HLA-G in patients under two distinct immunosuppression strategies after heart transplantation. Although CsA administration does not influence sHLA-G levels, RAD but not MMF is associated with sHLA-G expression. Larger prospective clinical investigations are required to confirm whether RAD is independently associated with increased HLA-G expression.