Transforming growth factor‐β (TGFβ) signaling requires phosphorylation of the type I receptor TβR‐I by TβR‐II. Although TGFβ promotes the association of TβR‐I with TβR‐II, these receptor components have affinity for each other which can lead to their ligand‐independent activation. The immunophilin FKBP12 binds to TβR‐I and inhibits its signaling function. We investigated the mechanism and functional significance of this effect. FKBP12 binding to TβR‐I involves the rapamycin/Leu–Pro binding pocket of FKBP12 and a Leu–Pro sequence located next to the activating phosphorylation sites in TβR‐I. Mutations in the binding sites of FKBP12 or TβR‐I abolish the interaction between these proteins, leading to receptor activation in the absence of added ligand. FKBP12 does not inhibit TβR‐I association with TβR‐II, but inhibits TβR‐I phosphorylation by TβR‐II. Rapamycin, which blocks FKBP12 binding to TβR‐I, reverses the inhibitory effect of FKBP12 on TβR‐I phosphorylation. By impeding the activation of TGFβ receptor complexes formed in the absence of ligand, FKBP12 may provide a safeguard against leaky signaling resulting from the innate tendency of TβR‐I and TβR‐II to interact with each other.