In vitro analyses have shown anti-HIV immunotoxins to be among the most effective AIDS antivirals tested. Because HIV has been continually selected by antibody, immunotoxins targeted to constant domains of viral antigens may not elicit drug-resistant mutants. A clinical trial with CD4-PE40, a possibly flawed immunotoxin with nonspecific toxicity and short serum half-life, has reduced interest in this form of therapy. It is proposed that the use of an immunotoxin directed against gp41 in combination with a CD4-Ig chimera is more likely to have a therapeutic effect than CD4-PE40. Clinical trials are also underway utilizing an immunotoxin that eliminates activated T-cells, an important cellular locus of HIV-replication.