Immunocytochemical staining experiments on filter paper or nitrocellulose models reveal that many, but not all, neurohormonal peptides, as well as poly-L-lysine, strongly bind a number of labeled reporter molecules, including colloidal gold- or peroxidase-labeled IgG, protein A, streptavidin, and albumin. Peptides displaying this type of (nonspecific) binding are basic; they include ACTH, VIP, opioid peptides, and poly-L-lysine. Pre-absorption of labeled probes with excess ACTH[1-24] or poly-L-lysine abolishes or greatly reduces binding not only to the homologous but also to the heterologous peptides tested. A number of cell types previously reported to display nonspecific immunoglobulin binding contain one or several of the basic neurohormonal peptides shown to display nonspecific absorption of labeled IgG, protein A, streptavidin, and albumin. This nonspecific absorption is reversed neither by high salt nor high pH conditions, nor by a number of detergents and blocking proteins. One dynorphin antiserum also displays nonspecific binding to the peptides as well as to pancreatic glucagon cells, and this nonspecific staining can be blocked by basic peptide pre-absorption (whether homologous or heterologous). These results suggest a need for caution when immunocytochemical studies of a number of basic polypeptides are interpreted, and also suggest the inclusion of novel control procedures in immunocytochemistry.