NogoA is a myelin-associated component that inhibits neurite outgrowth. Nogo66, a portion of NogoA, binds to Nogo66 receptor (NgR) and transduce the inhibitory signaling. The signal transduction of NgR requires LINGO-1 and p75, the low-affinity nerve growth factor receptor. However, Nogo signaling mechanism is poorly understood. Here we -observed that NgR and p75 were partitioned in low-density membrane raft fractions in forebrains, cerebella and cerebellar grannie cells. NgR interacted with p75 in lipid rafts. Localisation of p75 in lipid rafts was developmentally regulated. The portion of p75 in lipid rafts was much larger in adult rat brain than that in P8 brain. RhoA was also located in the lipid rafts of brain and cerebellar granule cells as well as cortical neurons. Treatment with lovastatin, an inhibitor of cholesterol biosynthesis, attenuated the Nogo66-induced inhibition of neurite outgrowth of cerebellar granule cells probably by decreasing the localization of RhoA in the lipid rafts and hence'blocking the Nogo66 signaling. In the further studies, we observed that disruption of lipid rafts by beta-methylcyclodextrin significantly reduced the localizaton of NgR and p75 in the lipid rafts as well as blocked the Nogo66 induced RhoA activation. In addition, we demonstrated that p75 was recruited into the lipid rafts by Nogo66 stimulation in PC 12 cells, Our results suggest'an important role of lipid rafts in facilitating the interaction between Nogo66 receptors and provide insight into mechanisms underlying the inhibition of neurite outgrowth by NogoA.