Background: Post-transplant immune reconstitution has a significantly effect on "hematopoietic stem cell transplantation (HSCT)" outcomes. Delay in immune reconstitution increases the risk of infections and disease relapse after transplantation. Recovery of T cells is mainly thymus-dependent. Thymic atrophy is associated with various clinical conditions that lead to a reduced thymic output. Therefore, thymus rejuvenation can improve immune reconstitution after transplantation. Zn plays a pivotal role in thymus rejuvenation. Zinc deficiency can lead to thymic atrophy, which increases susceptibility to infections. Zinc supplementation restores the immune system by boosting thymus output and T cell repertoire production. This protocol was designed to investigate the effect of oral zinc supplementation on T cell recovery in patients undergoing HSCT. Methods: Forty eligible candidates for autologous-HSCT will be selected. They will be randomly divided into "zinc" and placebo groups. Subsequently, they will receive three zinc or placebo tablets for the first 30 days post HSCT (+1 to +30), followed by one tablet or placebo for 60 days (+31 to +90). The copy numbers of "recent thymic emigrants (RTEs)" T cells and "T cell Receptor Excision Circles (TREC)" will be assessed before and after the intervention. All patients will be followed up for 365 days post HSCT for relapse and infection. Discussion: This clinical trial is the first to determine the efficiency of "zinc" in T cell recovery post HSCT. If successful, an available and inexpensive drug will improve immune system reconstruction after HSCT, reduce the risk of infection, particularly viral infections, and increase patient survival. Trial registration number: IRCT20191211045701N1