CD137 and its ligand are expressed in the BM, and conflicting data exist on the regulation of myelopoiesis by the CD137 receptor–ligand system. CD137−/− mice have increased numbers of myeloid cells in the BM, indicating an inhibitory influence of CD137 on myelopoiesis. However, CD137 also induces proliferation of hematopoietic progenitor cells and their myeloid differentiation, arguing for an enhancing effect. Here we hypothesized that this latter case represents the situation during infections since expression of CD137 is activation dependent and strongly enhanced during inflammation. Indeed, infections with Influenza, Bordetella pertussis, Mycobacterium bovis, Bacille Calmette-Guérin or Escherichia coli or i.p. injection of LPS led to increased numbers of CD137-expressing cells, especially of CD4+ T cells in the BM of mice. Coculture experiments confirmed that CD137 expression enables CD4+ T cells to induce proliferation and myeloid differentiation of BM and hematopoietic progenitor cells. CD137 also enhances myelopoiesis in vivo since the infection-induced increase in myeloid cell proliferation and total myeloid cell numbers in the BM were significantly lower in CD137−/− mice. This study reconciles earlier conflicting data by demonstrating that while CD137–CD137L interactions inhibit myelopoiesis during steady-state conditions they increase myelopoiesis during infection.