<p><i>Talaromyces marneffei</i> (TM) causes a deeply invasive fatal fungal disease in immunocompromised individuals that is widespread in Southeast Asia and southern China, and little is known about how this fungus can evade the human immune system. An imbalance between M1 and M2 macrophages plays a critical role in fungal clearance. However, whether regulatory T (Treg) cells mediate the immune evasion of TM by influencing the polarization direction of macrophages remains unexplored. In this study, we found that, compared with those in healthy volunteers, the number of circulating Treg cells in the peripheral blood and serum IL-10 levels were significantly increased in HIV-negative patients with talaromycosis and were positively correlated with the recurrence frequency and severity of talaromycosis. By establishing a mouse model of TM infection, we observed that persistent TM infection promoted M2 macrophage polarization and Treg differentiation in the lungs of mice. Notably, with the prolongation of the duration of TM infection, the continuous increase in both parameters was consistent. In vitro, we confirmed that TM infection promoted Treg cell activation and increased interleukin 10 (IL-10) secretion and that IL-10 activated and promoted STAT3 phosphorylation by binding to the IL-10 receptor (IL-10R), leading to increased M2 macrophage polarization and reduced iNOS production, ultimately diminishing the macrophage-mediated killing of TM. Taken together, the results of our study revealed that during TM infection, increased numbers of activated Treg cells promote macrophage polarization toward the M2 phenotype via the IL-10/IL-10R/STAT3 signaling pathway, leading to a decrease in the ability of macrophages to eliminate intracellular TM through the iNOS-mediated pathway, which causes persistent disseminated TM infection.</p>