We have recently reported a basic domain-mediated neurotoxic activity of HIV-1 Tat [1991, J. Virol. 65, 961-965]. Here we have tested the neurotoxicity in vivo of several Rev-related synthetic peptides and found that only those mimicking the basic regions of Rev from HIV-1, HIV-2 and SIV were lethal to mice. In contrast, the homologous domain of HTLV-1 Rex was found to be inactive for lethal activity. Analysis of the tropism of these peptides for phospholipids has demonstrated a direct interaction of the basic domain-containing peptides, except Rex, with acidic--but not neutral--phospholipids. As determined by circular dichroism, a possible correlation between the conformation of the basic regions and the toxicity is discussed.