Previous studies have described the isolation of monoclonal antibodies that neutralize human immunodeficiency virus type 1 (HIV-1). However, although certain antibodies are capable of blocking infection of CD4+ cells, the antibody-HIV-1 complex could potentially remain infectious and enter cells by an Fc receptor-mediated mechanism. Indeed, one goal of HIV-1 therapy with antibodies is the development of reagents capable of killing virus. The present studies with murine monoclonal antibody (MoAb) NM-01 demonstrate complement-mediated lysis of HIV-1. NM-01-dependent virolysis has been visualized by electron microscopy. Virus particles treated with NM-01 and rabbit or human complement undergo a process of outer envelope rupture and loss of the electron-dense core. The involvement of human complement in this process was confirmed by the presence of C9 in association with MoAb NM-01 immune complexes. In contrast, virolysis was not detectable with antibody or complement alone. Moreover, although MoAb NM-01 alone is capable of neutralizing HIV-1, the presence of rabbit complement was associated with over a 10-fold decrease in infectivity. Similar but less pronounced effects were observed with human complement. These findings support a potential role for antibody-dependent complement-mediated virolysis in HIV-1 therapy.