Ethanol extract of Bulgarian propolis (Et-Blg) was administered by oral route in doses ranging from 25 to 100mg/kg body weight in experimental Trypanosoma cruzi-infected Swiss mice. Treatment with 50mg Et-Blg/kg body weight/day led to a decrease in parasitemia and showed no hepatic or renal toxic effect. Treatment with Et-Blg led to a decrease in the spleen mass and modulated the initial inflammatory reaction as demonstrated by analysis of the leukocyte profile in peripheral blood, quantification of T cells subsets, and phenotypic markers in the spleen. Preferential expansion of CD8(+) and partial inhibition in the increase of CD4(+)CD69(+) and CD8(+)CD69(+) in CD4(+)CD44(+) and CD8(+)CD44(+) and in the decrease of CD8(+)CD62L in Trypanosoma cruzi-infected mice were also observed. Taken together, our data indicate that treatment of Trypanosoma cruzi-infected mice with Et-Blg interferes with the basic properties of immune cells.