Very few peripheral blood lymphocytes of seropositive individuals are presumably actively infected with human immunodeficiency virus type 1 (HIV-1). During coculture of lymphocytes of a seropositive individual with mitogen-stimulated normal peripheral blood lymphocytes, the number of infected cells becomes amplified such that detectable HIV-1 is produced. We report here that in addition to transmission by extracellular virus, cell-to-cell transmission is responsible for spreading HIV-1 infection from infected to uninfected cells. Azidothymidine and virus-neutralizing antibody had no effect on cell-to-cell transmission of HIV-1. Monoclonal antibodies to the CD4 receptor, but not to the CD3 receptor, prevented cell-to-cell transmission, which suggests that CD4 receptor-mediated cell fusion is involved in cell-to-cell transmission. Spread of infection in a cell-to-cell manner may be important in development of drug therapies for HIV-1 infection.