To assess the importance of gammadelta+ T lymphocyte responses in experimental murine cutaneous leishmaniasis, the expression of gammadelta+ TCR on the surface of lymphocytes in spleen and draining lymph nodes of mice infected with Leishmania major was examined. In both susceptible BALB/c and resistant CBA/J mice, an increase in gammadelta+ T cells was observed after s.c. infection. Whereas in chronically infected BALB/c mice, these cells can represent up to 35% of the CD3+ cells in the spleen, in CBA/J mice the percentage of gammadelta+ T cells returns to a lower level after resolution of lesions. Further experiments, in which the disease outcome was modified in susceptible BALB/c and in resistant CBA/J mice by chemotherapy or immunointervention, have confirmed that a correlation existed between the multiplication of the parasites and the expansion of gammadelta+ T cells in the spleen. Interestingly, in BALB/c mice infected for 4 mo, these gammadelta+ T cells represent 80% of the activated blast population and a large proportion of them express the alpha-chain of the CD8 molecule. In an attempt to assess a potential role for the gammadelta+ T cells in the control of infection with L. major, the effect of injection of mAb against gammadelta TCR on the course of infection was studied. In both BALB/c and CBA/J mice, blocking of the gammadelta TCR resulted in the development of larger lesions that contained increased numbers of parasites. This treatment significantly delayed the healing of cutaneous lesions in otherwise resistant CBA/J mice. Taken together these results indicate that gammadelta+ T cells are expanded during experimental infection of mice with L. major and could be involved in host defense against this parasite.