We report here the extended Phase I testing of d-ala-Peptide-T-amide (Peptide T) in open trial. The drug was given intravenously in doses ranging from 0.1 to 3.2 mg/kg/day to 14 acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) patients for 12 weeks. Following a 4-week off-drug period, the first 6 patients finishing the intravenous testing were continued on intranasal drug, 25 mg/day, for 8 weeks. Control subjects were tested on the same neuropsychologic tests, but did not receive drug. Minimal evidence of toxicity was found. Performance increments in cognitive and neuromotor function were observed in patients with moderate neuropsychologic impairment compared with controls. Changes in constitutional symptoms included weight gain averaging 2 kg and reported improved sense of well-being. The latter findings were independent of variation in cognitive and neuromotor function. Measures of immunologic function and antiviral activity did not change significantly during the study. These data provide a scientific rationale for Phase II testing of Peptide T in human immunodeficiency virus-1 (HIV-1) patients focusing on neuropsychiatric outcome.