Using a mouse model of bacterial infection, Baldridge et al. show that infection with Mycobacterium avium exerts a powerful stimulatory effect on haematopoietic stem cells, and that this stimulation is mediated by interferon-γ. Circulating immune cells in the blood are consumed during infection, and this work suggests that primitive stem cells in the marrow have a role in their replacement. These findings have implications for the use of interferon-γ as a therapeutic agent during chronic infections such as HIV/AIDS or tuberculosis and for recovery from bone marrow transplantation. Using a mouse model of Mycobacterium avium infection, it is shown here that interferon-γ regulates the proliferation of primitive haematopoietic cells during chronic infection. Lymphocytes and neutrophils are rapidly depleted by systemic infection1. Progenitor cells of the haematopoietic system, such as common myeloid progenitors and common lymphoid progenitors, increase the production of immune cells to restore and maintain homeostasis during chronic infection, but the contribution of haematopoietic stem cells (HSCs) to this process is largely unknown2. Here we show, using an in vivo mouse model of Mycobacterium avium infection, that an increased proportion of long-term repopulating HSCs proliferate during M. avium infection, and that this response requires interferon-γ (IFN-γ) but not interferon-α (IFN-α) signalling. Thus, the haematopoietic response to chronic bacterial infection involves the activation not only of intermediate blood progenitors but of long-term repopulating HSCs as well. IFN-γ is sufficient to promote long-term repopulating HSC proliferation in vivo; furthermore, HSCs from IFN-γ-deficient mice have a lower proliferative rate, indicating that baseline IFN-γ tone regulates HSC activity. These findings implicate IFN-γ both as a regulator of HSCs during homeostasis and under conditions of infectious stress. Our studies contribute to a deeper understanding of haematological responses in patients with chronic infections such as HIV/AIDS or tuberculosis3,4,5.