CD38 is a multifunctional ectoenzyme that behaves either as an enzyme, a cell adhesion molecule or as a cell surface receptor involved in cell signalling. It is expressed in cells of several lineages, including B and T lymphocytes, and macrophages. CD38 was shown to be important for the development of T-cell dependent humoral immune responses against extracellular pathogens. It also appears to be functionally important in macrophages, which are the host cells of Mycobacterium avium, an intracellular parasite that survives within these cells by avoiding a number of their microbicidal strategies. The present work aimed at investigating whether CD38 had any role on the immune response against mycobacterial infection. After intraperitoneal M. avium infection, the immune response of CD38KO mice was compared to that of their parental strain, C57Bl.6 mice. Absence of CD38 rendered mice more susceptible to mycobacterial infection. This susceptibility seems to be due to ineffective Th1 differentiation and polarization, which is essential for the control of M. avium infection. In addition, absence of CD38 seems to compromise the maintenance of the granulomatous barrier, leading to dissemination and unrestrained growth of mycobacteria.