In the present work, we analyzed the humoral response of Leishmania major experimentally infected BALB/c and C57BL/6 mice against three Leishmania antigens: total soluble antigen (soluble leishmania antigen(SLA)), a chimerical recombinant protein formed by the genetic fusion of four cytoplasmic proteins (PQ), and a kinetoplastic membrane protein (Kmp-11). We determined the correlation between the immune response against these proteins and the histopathological changes induced in the susceptible and resistant mice after infection. The data showed the existence of wide differences in the recognition of SLA, PQ, and Kmp-11 by the sera from both strains. The anti-SLA titer of BALB/c was 100 times higher than that of C57BL/6 mice. Antibodies against the recombinant Kmp-11 were detected only in infected BALB/c during the first stage of the infection. In contrast, the PQ protein was recognized by the sera from infected BALB/c mice but exclusively when they were in a late-lesion period. The data suggest that the response against the membrane Kmp-11 protein is transient and correlates with early developmental stages of the infection, whereas the response against cytoplasmic proteins as those present in PQ is sustained and could be considered as a marker of an advanced stage of the infection and disease.