Synaptic adhesion-like molecules (SALMs) are a recently discovered family of adhesion molecules that is widely distributed in the central nervous system and has been implicated in neurite outgrowth and synapse formation. To identify proteins that interact with extracellular domains of SALMs, we carried out yeast two-hybrid screening using the extracellular domain of SALM1 as bait. A clone encoding full-length reticulon 3A1 was isolated. This interaction was shown to occur through the LRR domain, which is found on all SALMs. To determine whether this relationship also occurs in brain, we performed immunoprecipitation using antibodies to SALMs 1-4. A 19-kDa band, identified as reticulon 3C, bound to all four SALMs, whereas a 90-kDa band, which did not comigrate with any known reticulon 3 variant, bound to SALMs 2 and 3. These results show that reticulon 3 may play a role in the trafficking of the SALM family of adhesion molecules.