Lymphocytes of human T-lymphotropic virus type-I (HTLV-I) infected patients were previously found tolerant to mitogenic stimuli as well as glucocorticoid treatment. These data suggest that common signaling events are impaired during this infection. The underlying mechanisms of these phenomena may include changes in cellular composition, cytokine milieu and the differential activation of mitogen-activated protein kinases (MAPKs). We investigated the role of (i) p38 and ERK MAPKs, (ii) lymphocyte subpopulations, (iii) and cytokines implicated in antigen or glucocorticoid-induced immunomodulation. Twenty-one asymptomatic carriers (AC), 19 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and 21 healthy subjects took part in this study. Lymphocytes were isolated and cultured in vitro to assess lymphocyte proliferation and sensitivity to dexamethasone. The expression of phospho-MAPKs, lymphocyte subsets and cytokines were assessed by flow cytometry. Patients with HAM/TSP had a higher p38/ERK ratio (p<0.05) associated with a reduced response to mitogens (phytohaemagglutinin or PMA+ionomycin) (p<0.001) and higher sensitivity to dexamethasone (p<0.05). HAM/TSP patients presented increased frequency of activated T cells and CD8(+)CD28(-) regulatory T cells, being negatively related to the mitogenic response. These data suggest that multiple underlying mechanisms could be involved with HTLV-related changes in cellular response to mitogens and glucocorticoids.