Receptor-mediated endocytosis of alpha 2M-protease complexes by normal human skin fibroblasts in culture was inhibited by the primary amines, methylamine and mono-dansylcadaverine. The latter was effective at a concentration two orders of magnitude lower than methylamine. Several observations indicated an intracellular mode of action of these amines, excluding interference with binding of alpha 2M to the receptor. Inhibition of endocytosis was dissociated from lysosomotropic effects of these amines by kinetic analysis of endocytosis. As opposed to chloroquine and alkaline incubation conditions (pH 8.0), the amines reduced the maximal rate of endocytosis considerably, indicating a reduction in number of available receptors. This was confirmed by measuring binding at 4 degrees C. Continuous recycling of receptors is indicated by the absence of down-regulation of number of receptors under conditions saturating for endocytosis of alpha 2M complexes. We postulate that the primary amines, methylamine and mono-dansylcadaverine, interfere with the recycling of alpha 2M receptors, while the chemical nature of the amines and the conditions under which inhibition becomes apparent point to the involvement of transglutaminase in this recycling.