Single and multiple doses of sCD4-PE40, a soluble recombinant fusion toxin selectively toxic to gp120-expressing cells, were evaluated in persons infected with human immunodeficiency virus type I (HIV-I). Seventeen of 24 patients who completed a single-dose safety trial were given either 1,5, 10, or 15 µg/kg of sCD4-PE40 by intravenous bolus once a month for 2 months, then weekly for 6 weeks. The weekly maximally tolerated dose was 10 µg/kg. The major toxicity was a transient dose-dependent elevation in hepatic aminotransferases peaking 48 h after infusion. Anti-Pseudomonas exotoxin antibody developed in 58% of recipients, and sera from 13 of 17 showed neutralizing activity against sCD4-PE40. No consistent changes in immunologic or virologic markers were observed. Weekly infusions of ⩽? 10 µg/kg of sCD4-PE40 are generally well tolerated, but additional studies correlating optimal dosing and frequency of administration with efficacy will be needed to define the role of this novel agent in the management of HIV-1-infected patients.