Delayed T cell recovery after allogeneic hematopoietic stem cell transplant (allo-HSCT) is an important contributor to transplant-related morbidity and mortality due to infection and malignant relapse. Optimal immune reconstitution requires a functional thymus, however, at the present time strategies to improve thymic reconstitution are limited. Zinc (Zn) is the second most abundant trace metal in the body, binding to more than 300 proteins. Zn deficiency is a clinical condition causing immunosuppression and thymic atrophy with a consequent reduction in the number of circulating recent thymic emigrants (RTEs). Furthermore, the role of Zn in tissue regeneration after damage has been clearly demonstrated in liver, skin, and intestinal diseases. In a pilot clinical trial, we previously demonstrated that patients receiving oral Zn supplementation after autologous HSCT showed increased thymic-dependent T cell reconstitution in the absence of adverse clinical events. Although a clear clinical benefit was observed, the mechanisms underlying this process are poorly understood. Thus, we used a murine model to evaluate the effect of Zn supplementation in thymic reconstitution after acute damage. Using a model of thymic damage caused by sub-lethal total body irradiation (SL-TBI, 550 cGy), we found that mice that received Zn supplementation demonstrated increased thymic cellularity when compared to untreated age-matched mice (Fig. 1a). Importantly, this finding was also confirmed in a clinically-applicable model of MHC-matched allogeneic HSCT (Fig. 1b). We have previously demonstrated endothelial cells (EC), which are extremely resistant to damaged, are able to trigger thymic endogenous reconstitution after damage by producing regenerative factors such as BMP4, which targets thymic epithelial cells (TECs), a key population crucial for T cell development. Interestingly, in our model of Zn administration, we found an increase in the number of regeneration-initiating ECs (Fig. 1c), and increased proliferation of TECs (Fig. 1d), which can occur in response to BMP4. Consistent with the hypothesis that Zn supplementation is activating the BMP4 pathway, thymic levels of BMP4 were increased at day +10 in zinc-treated mice (Fig. 2a, 2b), and, when stimulated in vitro for 24 hours with Zn sulfate, ex vivo propagated ECs (exECs) were directly induced to produce BMP4 (Fig. 2c), suggesting a likely mechanism by which Zn supplementation promotes thymic reconstitution. EC also express on their surface the Zn receptor GPR39 (Fig 3a), which is able to translate extracellular Zn signals in intracellular changes, and upregulate GPR39 expression after damage (Fig 3b). In conclusion, we demonstrate a mechanism by which zinc supplementation can improve thymic function and offers an innovative therapeutic strategy to improve T cell reconstitution in patients receiving allo-HSCT.