Our current understanding of the host immune response during leishmaniases largely derives from studies performed in mice due to the intrusive techniques required to study infected human patients. Swiss mice are highly resistant to Leishmania infections in concordance with observed response in humans, while BALB/c mice indicate a high-susceptibility phenotype. Developing a cross-breed between BALB/c and Swiss mice may have important consequences on disease development, immune responses and parasite killing, as yet, response of the cross-breed to Leishmania infection is superficial. The aim of the present study was to determine disease course and immune responses in F1 cross-breed between BALB/c and Swiss albino mice infected with L. major. Three mice groups were infected intradermally with stationary-phase L. major parasites with parental strains (BALB/c and Swiss albino) as controls. Lesion development was monitored weekly for 8 weeks and monocyte chemotactic protein (MCP-1), macrophage inflammatory protein (MIP-1α), interferon-gamma (IFN-γ) and IgG antibody quantified by enzyme-linked immunosorbent assay. The data were analysed using one-way analysis of variance and Tukey–Kramer test. Results indicated F1 mice having intermediate lesion sizes, type 1 cytokine levels and footpad parasite loads as compared to the parental strains. However, the F1 mice had low levels of IgG antibodies and parasite burden in the spleen. (P < 0.05). This study concludes that the F1 cross-breed between resistant and susceptible mice may be used as a requisite model to study the role of genetics in leishmaniases and perhaps other intracellular parasites.