Alpha-tocopherol plays an important role as a lipid-soluble antioxidant. It is present in all major mammalian cell types and shows tissue-specific distribution. This suggests the presence of specific proteins involved in intracellular distribution or metabolism of alpha-tocopherol. A diminution of tocopherol plasma concentrations contributes to the development of diseases such as vitamin E deficiency (AVED), atherosclerosis, and prostate cancer. Further evidence has been obtained for the existence of sites in cellular metabolism and signal transduction where alpha-tocopherol potentially plays a regulatory role. A signal transduction modulation specific for alpha-tocopherol has been described in several model systems. Using radioactively labeled alpha-tocopherol as tracer, we have isolated a new alpha-tocopherol-associated protein (TAP) from bovine liver. This protein has a molecular mass of 46 kDa and an isoelectric point of 8.1. From its partial amino acid sequence, a human gene has been identified with high homology to the newly described protein. Sequence analysis has established that the new TAP has structural motifs suggesting its belonging to a family of hydrophobic ligand-binding proteins (RALBP, CRALBP, alpha-TTP, SEC 14, PTN 9, RSEC 45). Human TAP has been cloned into Escherichia coli, and its tissue-specific expression has been assessed by Northern blot analysis.