It is widely believed that the gut, and particularly the lamina propria (LP) of the gut, contains most of the lymphocytes in humans. The strong depletion of CD4⁺ T cells from the gut LP of HIV-infected patients was, therefore, suggested to be such a large, irreversible insult that it could explain HIV disease progression. However, reviewing data from different mammalian species, we found that only 5%–20% of all lymphocytes reside in the gut, and that only 1%–9% of the total lymphocyte number is located in the gut LP. Our findings suggest that spleen and lymph nodes, rather than the gut, are the largest immune compartments in mammals.