Receptor expressed in lymphoid tissues (RELT) proteins are recently described surface receptors belonging to the larger TNF receptor family. To improve our understanding of RELT-mediated signal transduction, we performed a screen for RELT-interacting proteins. Phospholipid Scramblase 1 (PLSCR1) was identified through a yeast two-hybrid genetic screen utilizing the intracellular portion of the RELT family member, RELL1, as bait. PLSCR1 was observed to physically interact with all known RELT family members as determined by co-immunoprecipitation experiments. The protein kinase, oxidative stress responsive 1 (OSR1) was previously shown to interact and phosphorylate all three RELT family members. In our study, no physical association was observed between OSR1 and PLSCR1 alone. However, in the presence of RELT, OSR1 was capable of co-immunoprecipitating PLSCR1, suggesting the formation of a protein complex between RELT, OSR1, and PLSCR1. In addition, OSR1 phosphorylated PLSCR1 in an in vitro kinase assay, but only in the presence of RELT, suggesting a functional multiprotein complex. RELT and PLSCR1 co-localized in intracellular regions of human embryonic kidney-293 cells, with RELT overexpression appearing to alter the localization of PLSCR1. These studies demonstrate that RELT family members physically interact with PLSCR1, and that these interactions may regulate the phosphorylation of PLSCR1 by OSR1.