A phase 1 trial of a candidate human immunodeficiency virus type 1 (HIV-I) vaccine was done in 25 healthy seronegative subjects. The antigen, env2–3 (SF2), was a nonglycosylated polypeptide representing the gp120 region of the env gene of the HIV-l(SF2) isolate. It was produced in genetically engineered yeast as a denatured molecule incapable of binding CD4. A synthetic lipophilic muramyl tripeptide (MTP-PE) was used as an adjuvant. Ten subjects received adjuvant alone and 15 received 50- or 25O-µg doses of env2–3 (SF2) administered intramuscularly in two immunization regimens. In general, adjuvant and vaccine were well tolerated. Antibody responses to both the homologous antigen, env2–3 (SF2), and antigens from other highly divergent HIV isolates were elicited in the majority of vaccine recipients. However, antibody titers were low, without neutralizing activity. In 9 of 11 subjects who received the complete vaccine immunization series, a significant specific T lymphocyte response was observed.