[3H]CP-55,940, a high-affinity cannabinoid receptor ligand, was used for in vitro binding and autoradiography in peripheral tissues in the rat. Specific cannabinoid receptor binding was found to be restricted to components of the immune system, i.e., spleen, lymph nodes and Peyer's patches. Displacement studies showed that this binding is identical (similar Kd and structure-activity profile) to that in brain. Cannabinoid receptors in the immune system are confined to B lymphocyte-enriched areas, i.e., the marginal zone of the spleen, cortex of the lymph nodes and nodular corona of Peyer's patches. Specific binding is absent in T lymphocyte-enriched areas, such as the thymus and periarteriolar lymphatic sheaths of the spleen. Certain macrophage-enriched areas, i.e., liver and lung, lack specific binding. Thus, the single peripheral cell type that may contain cannabinoid receptors is the B lymphocyte. Numerous sites have dense binding that could not be displaced by excess unlabeled drug. These nonspecific sites were found in the liver, adrenal glands and sebaceous glands, which are high in fat content, and in the heart, pancreas, components of the male and female reproductive systems and the epithelium of the esophagus. Thus, the highly lipophilic nature of cannabinoids does not appear to be the sole determinant of nonspecific binding. The data suggest that cannabinoids may exert specific receptor-mediated actions on the immune system of rats. Perhaps, also at high concentrations, cannabinoids exert membrane effects at sites where they are sequestered nonspecifically.