In vitro studies have pointed to the collapsin response mediator proteins (CRMPs) as key regulators of neurite outgrowth and axonal differentiation. CRMP3 is expressed mostly in the nervous system during development but remains at high levels in the hippocampus of adults. To explore CRMP3 function in vivo, we generated mice with targeted disruption of the CRMP3 gene. Immunohistochemistry and Golgi staining of CA1 showed abnormal dendrite and spine morphogenesis in the hippocampus of CRMP3-deficient mice. Apical dendrites displayed an increase in undulation and a reduction in length and branching points. Basal dendrites also exhibited a reduction in length with an alteration in soma stem distribution and an increased number of thick dendrites localized in stratum oriens (SO). Long-term potentiation (LTP) was impaired in this area. These data indicate an important role for CRMP3 in dendrite arborization, guide-posts navigation, and neuronal plasticity.—Quach, T. T., Massicotte, G., Belin, M. F., Honnorat, J., Glasper, E. R., Devries, A. C., Jakeman, L. B., Baudry, M., Duchemin, A. M., Kolattukudy, P. E. CRMP3 is required for hippocampal CA1 dendritic organization and plasticity.