The role of the endogenous interleukin-10 (IL-10) in the control of Mycobacterium bovis Bacille Calmette Guerin (BCG) infection was assessed using IL-10-deficient (IL-10-/-) mice. Similar to wild-type (WT) mice, IL-10-/- mice were resistant to intravenous challenge with Mycobacterium bovis BCG. Significantly higher plasma concentrations of IL-12 and tumour necrosis factor (TNF) indicated an elevated protective immune response of IL-10-/- mice. Determination of bacilli burden in IL-10-/- mice showed accelerated clearance in the lungs, spleen and the liver in comparison to WT mice. Enhanced inflammation and a vigorous granulomatous response accompanied accelerated mycobacterial clearance. Immunohistochemical analysis of hepatic granulomas from IL-10-/- mice revealed augmented lymphocyte recruitment and macrophage activation, such as increased major histocompatibility complex (MHC) class II and inducible nitric oxide synthase (iNOS) expression. Further, it was found that enlarged granulomas persisted subsequent to mycobacterial clearance and failed to resolve in the absence of IL-10. In conclusion, endogenous IL-10 dampens the cell-mediated immune response to mycobacterial infection.