P75 and the Nogo receptor (NgR) form a signaling unit for myelin-inhibitory molecules, with p75 being responsible for RhoA activation. Since p75 lacks the GEF domain, it has remained unclear how p75 activates RhoA. Here, we report that Kalirin 9, a dual RhoGEF, binds p75 directly, and regulates p75-NgR-dependent RhoA activation and neurite inhibition in response to MAG. The region of p75 that Kalirin9 binds includes its mastoparan-like fifth helix, which was shown to recruit RhoGDI-RhoA. As predicted from the presence of a shared binding site, we found that Kalirin9 competes with RhoGDI for p75 binding in a dose-dependent manner in vitro. In line with these data, MAG addition to cerebellar granule neurons resulted in a reduction in the association of Kalirin9 with p75, and a simultaneous increase in the binding of RhoGDI to p75. These results reveal a mechanism by which the fifth helix of p75 regulates RhoA activation.