Human immunodeficiency virus (HIV) envelope glycoprotein interactions with cell surface CD4 are involved in both virion infectivity and virally mediated cell fusion. D-mannose-specific lectins such as Con A specifically blocked virion infectivity and cell fusion. Studies with a recombinant vaccinia virus containing the HIV envelope gene demonstrated that Con A-mediated inhibition of HIV-induced fusion involved lectin binding to the viral envelope glycoprotein. These results indicate the importance of envelope glycosylation in the pathobiology of HIV infection, and suggest potential mechanisms for interfering with HIV infectivity and cytopathology.