Natural killer cell activity was compared in the Long-Sleep and Short-Sleep mouse lines. These mice, initially selected for their sensitivities to a hypnotic dose of ethanol, are also differentially sensitive to other agents which act through the benzodiazepine/GABA receptor chloride ionophore complex. Natural killer cell activity was 40-59% lower in Short-Sleep when compared to Long-Sleep mice. Flow cytofluorometric analysis demonstrated that the number of Nk-1+ cells was also lower in the spleens of Short-Sleep than Long-Sleep mice. In addition, the incidence of 3-methylcholanthrene-induced tumors was significantly greater in Short-Sleep (85.7%) than in Long-Sleep (14.3%) mice. These results suggest that the Long-Sleep and Short-Sleep mouse lines may represent a unique model to assess the physiological role of the benzodiazepine/GABA receptor chloride ionophore complex in the neural modulation of immune function.