Immunogenicity and efficacy of pre-erythrocytic malaria vaccine candidates, such as RTS,S and radiation attenuated sporozoites (RAS), has been shown to be severely compromised in clinical trials conducted in endemic regions compared to the United States. In this study, we measured the effect of prior exposure to blood stage malaria on preerythrocytic vaccine efficacy using a circumsporozoite surface protein (PyCSP) vaccine candidate in the Plasmodium yoelii 17XNL murine model of malaria. Immunization with PyCSP delivered in Montanide ISA 51 adjuvant induced antibody-dependent sterilizing immunity against sporozoite challenge in C57BL/6 mice. However, prior exposure of PyCSP vaccinated mice to blood stage malaria resulted in a significant increase in intrahepatic parasite burden after sporozoite challenge demonstrating that blood stage malaria impaired the protective efficacy of PyCSP. This loss of vaccine efficacy caused by prior exposure to blood stage malaria was accompanied by a threefold reduction in IgG1 antibody titers. Results of an ELISpot assay performed 14 weeks after vaccination indicate that prior exposure to blood stage malaria causes a significant contraction of the memory B cell response to PyCSP. This model can be used to identify novel immune regulatory pathways induced by blood stage malaria that compromise pre-erythrocytic vaccine efficacy