Updated project metadata. The development of a prophylactic vaccine for Kaposi sarcoma-associated Herpesvirus (KSHV) would prevent consequences from infection including disorders such as Kaposi sarcoma and primary effusion lymphoma. Here, we study the immunogenicity of noninfectious virus-like vesicles (VLVs) of KSHV as a potential future vaccine platform. VLVs present a repertoire of viral structural proteins but are noninfectious due to a defect in capsid formation that prevents viral DNA packaging. Immunization of mice with adjuvanted VLVs results in virus-specific antibodies and T cells. These antibodies neutralize viral infection, and this neutralization is enhanced by the complement system. Complement-enhanced neutralization is dependent on antibodies targeting the SCR region of viral ORF4. However, this activity was not present in serum from KSHV-infected humans. Our study highlights an important role of antibody effector functions in the development of a future KSHV vaccine