Gynecomastia is very common cause of a patient’s visit to a mastology office. Gynecomastia is experienced in up to 70% of mid-puberty males and in up to 65% of middle-aged men. The treatment starts with the identification of the cause, but in most cases the patient is treated with tamoxifen, aromatase inhibitors, liposuction or surgery. Τreatment of gynecomastia is not well standarized. In our prospective study, we examined the use of tamoxifen followed by letrozole and a clinically important reduction was achieved, when compared with those who were treated only with tamoxifen. Further research needs to be conducted in order to confirm this promising protocol.