Rationale: Patients with chronic Schistosoma mansoni infection show lower anti-soluble egg antigen (SEA) proliferation responses and higher responses to soluble worm antigen preparation (SWAP). Objective: To compare the activation status and proliferation response of peripheral blood mononuclear cells (PBMC) of infected (XTO) and egg-negative individuals (NI) living in the same endemic area. Methods: XTO (n = 51) and NI individuals from the same geographical area (n = 37) and healthy blood donors (n = 22) were evaluated before and after stimulation with SEA and SWAP. The expression of activation markers (CD4+ HLADR+, CD8high+HLA-DR+ and CD8+ CD28+) and proliferation assay was assessed by flow cytometry. Findings: PBMC from infected patients showed lower frequency of CD4+ but no change in CD8+ T cells when compared with the healthy donor group. The ratio CD4+/CD8+ was 1.3, 0.6 and 0.5 in healthy donors, infected and non-infected individuals, respectively. The HLA-DR+ expression on CD8+ was higher in PBMC from infected and non-infected individuals than from healthy donors, but similar in both total lymphocytes and CD4+ populations. No intergroup proliferation response differences were observed in CD4+ and CD8+ PBMC unstimulated and stimulated with SEA and SWAP. The SEA but not SWAP-stimulated cells showed a decrease in the expression of phosphorylated extracellular signal-regulated kinase (ERK1/2). Conclusions: XTO and NI individuals living in the same area presented a smaller per cent of CD4+ and a higher per cent of CD8+ cells. The activation by either CD8high+HLA-DR+ or CD8high+HLA-DR+/CD8+ was enhanced and decreased in XTO and NI by CD8+ CD28+ and CD8+ CD28+/CD8+ when compared with healthy donor. ERK phosphorylation was attenuated in XTO and NI individuals when stimulated with SEA but not SWAP.