We examined the in vitro effects of ethyl alcohol and a recombinant HIV- 1, fusion peptide, env-gag, corresponding to portions of the gp-41 envelope (env) and internal core (gag) proteins on the natural killer (NK) cell activities of lymphocytes from healthy donors. Proculture of large granular lymphocytes (LGL) from normal donors with 0.3% alcohol for 72 hr significantly inhibited NK activity compared to untreated controls. Direct addition, without preculture, of alcohol (0.1%, 0.2% and 0.3%) and env-gag peptide (10 ng/ml) at concentrations which did not affect NK activity when either was added alone, produced a significant, synergistic, inhibitory effect on NK activity when added together. This synergistic effect of alcohol and HIV-derived soluble products is consistent with a model proposing that alcohol abuse may be a co-factor involved in the progression of HIV infections.