T cells, which constitute an essential arm in the adaptive immunity, complete their development in the thymus through a process called thymopoiesis. However, thymic involution can be induced by a couple of factors, which impairs T cell functions and is slow to recover. Therefore, understanding how thymopoiesis is regulated may lead effort to accelerate thymic recovery and improve immune functions in thymocyte-depleted patients. In this project, we identified scavenger receptor BI (SR-BI), a high density lipoprotein (HDL) receptor, as a novel modulator in thymopoiesis. In mice, absence of SR-BI causes a significant reduction in thymus size after puberty and a remarkable decrease in thymic output. Consequently, SR-BI-null mice show a narrowed naïve T cell pool in the periphery and blunted T cell responses, indicating that the impaired thymopoiesis due to SR-BI deficiency leads to compromised T cell homeostasis and functions. The impaired thymopoiesis of SR-BI-null mice is featured by a significant reduction in the percentage of earliest T progenitors (ETPs) but unchanged percentages of other thymocyte subtypes, suggesting that SR-BI deficiency causes a reduction in progenitor thymic entry. Further investigations reveal that SR-BI deficiency impairs thymopoiesis through affecting bone marrow progenitor thymic homing without influencing the lymphoid progenitor development in bone marrow. Importantly, SR-BI-null mice exhibit delayed thymic recovery after sublethal irradiation, indicating that SR-BI is also required for thymic regeneration. Using bone marrow transplantation models, we elucidate that it is non-hematopoietic rather than hematopoietic SR-BI deficiency that results in the defects in thymopoiesis. However, SR-BI deficiency-induced hypercholesterolemia is not responsible for the impaired thymopoiesis. Using adrenal transplantation models, we found that absence of adrenal SR-BI is responsible for the impaired thymopoiesis, as shown by that adrenalectomized mice transplanted with SR-BI-null adrenal gland display reduced thymus size, decreased percentage of ETPs and delayed thymic regeneration compared with those transplanted with wild-type adrenal. Altogether, results from this study elucidate a previously unrecognized role of SR-BI in thymopoiesis. We reveal that SR-BI expressed in adrenal gland is critical in maintaining normal T cell development and enhancing thymic regeneration, providing novel links between adrenal functions and T cell development.