Although the adaptive immune response almost invariably fails to completely eliminate retroviral infections, it can exert significant protection from disease and long-term control of viral replication. Friend virus (FV), a mouse retrovirus, causes persistent infection in all strains of mice and erythroleukaemia in susceptible strains, the course of which can be strongly influenced by both genetic and extrinsic factors. In this study we examine the impact of coinfection on the requirements for immune control of FV infection. We show that congenic C57BL/6 mice, in which the introduction of an allele of the Friend virus susceptibility 2 gene provides the potential for FV-induced leukemia development, effectively resist FV infection, and both T cell- and Ab-dependent mechanisms contribute to their resistance. However, we further demonstrate that coinfection with lactate dehydrogenase-elevating virus (LDV) renders these otherwise immunocompetent mice highly susceptible to FV infection and subsequent disease. The presence of LDV delays induction of FV-specific neutralizing Abs and counteracts the protective contribution of adaptive immunity. Importantly, the disease-enhancing effect of LDV coinfection requires the presence of a polyclonal B cell repertoire and is reproduced by direct polyclonal B cell activation. Thus, immune activation by coinfecting pathogens or their products can contribute to the pathogenicity of retroviral infection.