Objective To investigate the effect and mechanism of high-dose clodronate liposomes (CL) treatment on the growth of Plasmodium yoelii 17XL (Py17XL) in mice. Methods Sixty one female BALB/c mice were randomly assigned to five groups: high dose CL treatment group (CL treatment group, 23 mice) and control liposome treatment group (29 mice), healthy CL treatment group (3 mice) and healthy control liposome treatment group (3 mice), and blank control group (3 mice). The CL treatment group mice (23) were injected via tail vein with high-dose CL (5 μg/μl 200 μl) on d1 prior to infection and on d2 and d5 post-infection of Py17XL respectively; the control liposome treatment group mice (29) were injected intravenously with the same volume of control liposome at the respective time points. The healthy CL treatment group mice (3) and the healthy control liposome treatment group mice (3) were given intravenously with high-dose CL (5 μg/μl 200 μl) or the same amounts of control liposomes at the corresponding time points. The blank control group mice (3) were not treated. Tail vein blood samples from the mice of CL treatment group and control liposome treatment group(5 mice each) were collected daily post-infection, of which the smears were examined microscopically for estimating parasitemia and survival rate. Spleen samples were collected from the two groups on d0, d3 and d6 post-infection, and then the splenic lymphocytes were isolated to detect the proliferation of Plasmodium-specific CD4 ⁺ T cell and CD8⁺ T cells and the secretion of interferon γ (IFN-γ) using flow cytometry. The mice serum IgG antibodies against Plasmodium were determined by enzyme-linked immunosorbent assay (ELISA) on d6 post-infection. On d2, d4 and d6 post-infection, spleen lymphocytes of the CL treatment group, control liposome treatment group and blank control group (3 mice each time) were isolated, and the cell types depleted by CL were determined by flow cytometry. Plasmodium infection in the spleen dendritic cells of the control liposome treatment group (2 mice each time) was microscopically observed by Giemsa staining. Results In both the CL treatment group and control liposome treatment group, mice death occurred on d7 post-infection (2 in CL treatment group, 3 in control liposome treatment group), and all mice died on d8 post-infection, with no significant difference between the groups (χ ² = 0.360, P > 0.05). After infection, the parasitemia in the CL treatment group was apparently lower than that in control liposome treatment group. On d6 post-infection, the parasitemia in the CL treatment group (34.537 ± 8.165)%, was significantly different from that in the control liposome treatment group (61.303 ± 8.799)% (F = 1.821, P < 0.05). On d2, d4 and d6 post-infection, the spleen cell responses in the CL treatment group were assayed, showing that the proportions of CD11b ⁺ monocytes in the spleen were (6.240 ± 0.605)%, (8.277 ± 0.411)%, (6.573 ± 0.246)%, and that of CD11c ⁺ dendritic cells in the spleen were (3.700 ± 0.599)%, (8.003 ± 0.655)%, (3.920 ± 0.534)%, and that of F4/80 ⁺ macrophages in the spleen were (4.830 ± 0.695)%, (11.007 ± 1.121)%, (2.743 ± 0.395)%, respectively, which were significantly lower than those in the control liposome treatment group (F = 5.945, 2.075, 7.091, P < 0.05). On d3 and d6 post-infection, no statistical differences were found in proliferation of Plasmodium-specific CD4 ⁺ T cells and CD8⁺ T cells, and secretion of IFN-γ between the CL treatment group and control liposome treatment group (P > 0.05). On d6 post-infection, the 10-fold-diluted serum IgG antibody level against Plasmodium in the CL treatment group (2.241 ± 0.056) was significantly lower than that of the control liposome treatment group (2.490 ± 0.090) (F = 27.66, P < 0.05). Microscopic examination indicated that no Plasmodium was observed by Giemsa staining in the CD11c⁺ cells of the control liposome treatment group on d2 and d4 post-infection, however, a large number of Plasmodium was found in almost all CD11c ⁺ cells on d6 post-infection. Conclusion After the macrophages, dendritic cells and monocytes were drained by high-dose CL intervention, regulation via innate immunity and adaptive immunity response against erythrocytic stage of Plasmodium in the mice may not involve in the suppression of Py17XL proliferation and growth.