In general, plasma membrane integral proteins, such as the membrane-anchored growth factor proTGF-α, are assumed to be transported to the cell surface via a nonregulated, constitutive pathway. proTGF-α C-terminal mutants are retained in an early secretory compartment. Here, using a two-hybrid screen, we identify two TACIPs (proTGF-alpha cytoplasmic domain–interacting proteins) that contain PDZ domains and do not interact with proTGF-α C-terminal mutants. The binding specificity of one of them, TACIP18 (previously identified and named Syntenin or mda-9), coincides with that of the component that possibly mediates the normal trafficking of proTGF-α. TACIP18 colocalizes and interacts specifically with immature, intracellular forms of proTGF-α. Therefore, it appears that the interaction of TACIP18 with proTGF-α in the early secretory pathway is necessary for the targeting of the latter to the cell surface.