A characteristic feature of COVID-19 disease is lymphopenia. Lymphopenia occurs early in the clinical course and is a predictor of disease severity and outcomes. The mechanism of lymphopenia in COVID-19 is uncertain. It has been variously attributed to the release of inflammatory cytokines including IL-6 and TNF-alpha; direct infection of the lymphocytes by the virus; and rapid sequestration of lymphocytes in the tissues. Additionally, we postulate that prostaglandin D2 (PGD2) is a key meditator of lymphopenia in COVID-19. First, SARS-CoV infection is known to stimulate the production of PGD2 in the airways, which inhibits the host dendritic cell response via the DP1 receptor signaling. Second, PGD2 is known to upregulate monocytic myeloid-derived suppressor cells (MDSC) via the DP2 receptor signaling in group 2 innate lymphoid cells (ILC2). We propose targeting PGD2/DP2 signaling using a receptor antagonist such as ramatroban as an immunotherapy for immune dysfunction and lymphopenia in COVID-19 disease.