The 14-base pair (bp) polymorphism within the HLA-G gene has been investigated in heart transplant patients for the first time. The 14-bp polymorphism is associated with HLA-G mRNA stability and the patterns of alternative isoforms splicing, and therefore may influence the functionality of the HLA-G molecule. In heart transplantation, the highest production of soluble HLA-G was related to the -14/-14-bp genotype in the pre- and post-transplantation periods. Our study findings showed that the 14-bp polymorphism of the HLA-G gene influenced the expression of soluble HLA-G in heart transplantation and accordingly resulted in low rejection rates, being a possible marker of genetic variability associated with heart transplantation. In addition, the 14-bp polymorphism of the HLA-G gene is related to the absorber status of cyclosporine of each individual patient, and is useful for determining the oral dose of cyclosporine to manage patients (to adjust immunosuppressive protocols) so as to minimize the risk of a low or high immunosuppression and the side effects in the early stages of heart transplantation.