Ongoing outbreaks of filoviruses in Africa and concerns about their use in bioterrorism attacks have led to intense efforts to find safe and effective vaccines to prevent the high mortality associated with these viruses. We previously reported the generation of virus-like particles (VLPs) for the filoviruses, Marburg (MARV) and Ebola (EBOV) virus, and that vaccinating mice with Ebola VLPs (eVLPs) results in complete survival from a lethal EBOV challenge. The objective of this study was to determine the efficacy of Marburg VLPs (mVLPs) as a potential vaccine against lethal MARV infection in a guinea pig model. Guinea pigs vaccinated with mVLPs or inactivated MARV developed MARV-specific antibody titers, as tested by ELISA or plaque-reduction and neutralization assays and were completely protected from a MARV challenge over 2000 LD50. While eVLP vaccination induced high EBOV-specific antibody responses, it did not cross-protect against MARV challenge in guinea pigs. Vaccination with mVLP or eVLP induced proliferative responses in vitro only upon re-exposure to the homologous antigen and this recall proliferative response was dependent on the presence of CD4+ T cells. Taken together with our previous work, these findings suggest that VLPs are a promising vaccine candidate for the deadly filovirus infections.