In order to investigate the mechanism of uptake of meta-iodobenzylguanidine (mIBG) by the adrenal glands, autoradiographic and pharmacologic studies were performed in mice and dogs receiving radioiodinated mIBG. In mice, on macroautoradiography of whole body sections 48 h after 125I-mIBG, most of the radioactivity was focused in the adrenal glands. On microautoradiography, silver grains were exclusively located in the adrenal medulla. Tissue counting after phenoxybenzamine, cocaine, and desipramine treatment resulted in 45%, 35%, and 0% inhibition of mIBG uptake, respectively. Tissue counting and scintigraphic studies demonstrated a more than 50% mIBG release from the adrenal glands after reserpine. These data indicate the high affinity of mIBG for adrenal medulla and suggest that the mIBG and catecholamine uptake mechanisms are only partially the same.