Paracoccidioidomycosis (PCM) is the most prevalent deep mycosis in Latin America and presents a wide spectrum of clinical manifestations. We established a genetically controlled murine model of PCM, where A/Sn mice develop an infection which mimics the benign disease (immune responses which favor cellular immunity) and B10.A animals present the progressive disseminated form of PCM (preferential activation of B cells and impairment of cellular immune responses). To understand the immunoregulatory phenomena associated with resistance and susceptibility in experimental PCM, A/Sn and B10.A mice were studied regarding antigen-elicited secretion of monokines (TNF-<FONT FACE="Symbol">a</font> and TGF-ß) and type-1 (IL-2 and IFN-<FONT FACE="Symbol">g</font>) and type-2 (IL-4,5,10) cytokines. Total lymph node cells from resistant mice infected ip with P. brasiliensis produced early and sustained levels of IFN-<FONT FACE="Symbol">g</font> and IL-2; type-2 cytokines (IL-4 and IL-5) started to appear 8 weeks after infection. In contrast, susceptible mice produced low levels of IFN-<FONT FACE="Symbol">g</font> concomitant with significant levels of IL-5 and IL-10 early in the infection. In the chronic phase of the disease, susceptible animals presented a transitory secretion of IL-2, and IL-4. In the pulmonary infection IL-4, IL-5 and IL-10 were preferentially detected in the lung cells washings of susceptible animals. After in vitro challenge with fungal antigens, normal peritoneal macrophages from B10.A mice secreted high levels of TGF-ß and low levels of TNF-<FONT FACE="Symbol">a</font>. In contrast, macrophages from A/Sn animals released high levels of TNF-<FONT FACE="Symbol">a</font> associated with a small production of TGF-ß. The in vivo depletion of IFN-<FONT FACE="Symbol">g</font> not only abrogated the resistance of A/Sn mice but also diminished the relative resistance of B10.A animals. The in vivo depletion of IL-4 did not alter the disease outcome, whereas administration of rIL-12 significantly enhanced resistance in susceptible animals. Taken together, these results suggest that an early secretion of high levels of TNF-<FONT FACE="Symbol">a</font> and IFN-<FONT FACE="Symbol">g</font> followed by a sustained secretion of IL-2 and IFN-<FONT FACE="Symbol">g</font> plays a dominant role in the resistance mechanisms to P. brasiliensis infection. In contrast, an early and ephemeral secretion of low levels of TNF-<FONT FACE="Symbol">a</font> and IFN-<FONT FACE="Symbol">g</font> associated with production of IL-5, IL-10 and TGF-ß characterizes the progressive disease of susceptible animals.