CD4(178)-PE40 is a recombinant protein consisting of a portion of human CD4 linked to active domains of Pseudomonas aeruginosa exotoxin A. In previous experiments with human T cell lines, the hybrid toxin was found to selectively kill cells infected with human immunodeficiency virus type 1 (HIV-1), and to inhibit HIV-1 spread in mixtures of infected and uninfected cells. CD4(178)-PE40 inhibits HIV-1 spread in cultured primary human lymphocytes. Moreover, the hybrid toxin selectively kills HIV-1 chronically infected monocyte/macrophage cell lines and inhibits HIV-1 spread in primary macrophage cultures. Control experiments indicate that the protective effects of CD4(178)-PE40 against HIV-1 spread are due to selective killing of the infected cells rather than simply to neutralization by the CD4 moiety. Thus, for the major cell types susceptible to HIV infection in vivo, surface envelope glycoprotein is expressed at sufficient levels to enable binding and internalization of CD4(178)-PE40 and consequent selective cell killing.