Interleukin (IL)‐10 is an immunoregulatory cytokine that inhibits both Th1‐like T cell responses and macrophage activation. Deficiency of IL‐10 has been associated with increased Th1‐like CD4⁺ T‐cell responses and increased clearance of some intracellular pathogens, however, its role in mycobacterial infections is controversial. In order to examine the effects of mycobacterial virulence on the outcome of infection we compared infection with Mycobacterium avium and virulent Mycobacterium tuberculosis in C57Bl/6 IL‐10^−/– mice. M. avium infection in IL‐10^−/– mice resulted in sustained increases in interferon (IFN)‐γ‐secreting T‐cell responses and was associated with the increased clearance of M. avium from the liver and lung. By contrast, M. tuberculosis infection in IL‐10^−/– mice led to a transient increase in IFN‐γ T‐cell responses at 4 weeks postinfection, with reduced bacterial burden in the lungs. This was not sustained so that by 8 weeks there was no difference to wild‐type (WT) mice. In vitro infection of IL‐10^−/– macrophages with M. avium, but not M. tuberculosis, led to an increased IL‐12 production. Therefore, endogenous IL‐10 exerts a significant inhibition on specific IFN‐γ T‐cell responses to M. avium infection, however, this effect is short lived during the M. tuberculosis infection, and fails to influence the long‐term course of infection.