The lymphocyte proliferative responses were studied of 12 volunteers enrolled in a phase I trial of a baculovirus-expressed recombinant human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (rgp160) vaccine. Six subjects received rgp160 and three subjects each received recombinant hepatitis B vaccine or placebo at 0, 1, and 6 months. rgp160 and a control preparation, baculovirus-expressed recombinant HIV-1 p24, were used as in vitro antigens. At day 56, all rgp160 recipients had stimulation indexes (rgp160/rp24) > 3.0, and five of six had differences in counts per minute (cpm) > 1000. Stimulation indexes were < 2.0 and cpm differences were < 150 in all six who did not receive rgp160. Lymphocyte proliferative responses were first noted 2 weeks to 5 months before initial Western blot reactivity and persisted for greater-than-or-equal-to 540 days, even among subjects who lost detectable antibody. Thus, the HIV-1 rgp160 vaccine induces persistent cellular immune recognition as demonstrated by lymphocyte proliferation.