Abstract Strategies for purging persistent reservoirs in human immunodeficiency virus (HIV)-infected individuals may be enhanced by including agents that specifically kill virus-expressing cells. Anti-HIV envelope immunotoxins (ITs) represent one class of candidate molecules that could fulfill this function. We have previously utilized an anti-gp120 IT in conjunction with various stimulants to kill latently infected T cells ex vivo. Here we show that primary macrophages expressing HIV Env are relatively refractory to killing by IT when used alone. However, including stimulants such as prostratin or granulocyte-macrophage colony-stimulating factor to increase HIV gene expression in infected macrophages enhanced IT-mediated killing. Therefore, "activation-elimination" strategies similar to those proposed for purging the latent HIV reservoir may prove useful in clearing chronically infected macrophages in vivo.