Leishmania major infected BALB/c mice were treated with N-acetyl-l-cysteine (NAC), a glutathione precursor, to evaluate the role of in vivo glutathione on lesion pathology and cytokine profiles following infection. Mice were maintained on NAC-containing water 2 days before infection for a total of 14 weeks. The BALB/c response to L. major infection was improved by oral administration of NAC, at the level of histopathological outcome, lesion progression and cytokine profile. A significantly improved histopathological outcome of the footpad lesion, characterized by a mixed inflammatory infiltrate organized in a focal pattern with little tissue destruction and a reduced parasite load, was observed in NAC-treated BALB/c mice. Histopathological modulation was accompanied by a modified cytokine pattern from popliteal lymph node cells, demonstrated by a sustained higher frequency of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha)-producing cells. This work points to an important role for glutathione in the modulation of effector responses in BALB/c mice.