Low density lipoprotein receptor-related protein (LRP) is a multi-functional receptor which mediates the endocytotic uptake of several ligands implicated in neuronal pathophysiology. In this study, LRP expression and localization, in cultured hippocampal neurons from 18-day-old rats, were examined by immunofluorescence microscopy. LRP was restricted to the cell bodies and dendrites of mature neurons, where it was uniformly distributed on both dendritic shafts and spines. Immunoreactive protein was detected within the first 24 h of culture and acquired a polarized distribution by the end of the first week. Expression of LRP mRNA by the cultured neurons was demonstrated by Northern blot analysis. Binding studies with the LRP ligand, activated alpha2-macroglobulin, confirmed that LRP was present and functional on the hippocampal neuron cell surface. These studies demonstrate that neuronal LRP undergoes selective compartmentation during neuronal maturation and suggest that LRP-mediated endocytosis is largely restricted to the somatodendritic compartment.