The objective of this study was to analyse the modulatory effect of proteins released by cultured Leishmania infantum promastigotes on the cellular immune response of infected susceptible (BALB/c) and more resistant (C57BL/6) mice strains after 30 and 45 days of infection. One month after parasite inoculation, L. infantum released protein fractions (High, Inter, and Low according to molecular weight) stimulated C57BL/6 mice spleen cells to proliferate and to express cytokines. Following the decrease of parasite load only the Low protein fraction induced a considerable release of IL-4. In BALB/c mice, specific immune response to protein fractions was only observed at the higher parasitic level, with the fraction Inter promoting the production of IL-4 and fractions High and Low inducing high levels of IL-12. These results point out to a role of these proteins fractions in the modulation of host immunity, that depending on the host genetic background and parasite magnitude, seem to be critical in the control of parasite replication levels, thus avoiding premature host death.