The transmembrane 4 superfamily (TM4SF) comprises an assemblage of surface antigens from mammalian cells and from the human blood flukes. Member proteins of the TM4SF are characterized by the presence of four hydrophobic domains, which are presumed to be membrane-spanning, and specific conserved motifs. The Sm23 group of TM4SF, which includes Sm23, Sj23, and Sh23 from blood flukes, shows potential as immunodiagnostic and vaccine target antigens for use in controlling human schistosomiasis. Here we describe a cDNA from miracidia and adult Schistosoma japonicum parasites which apparently encodes a new member of the TM4SF. The deduced polypeptide, termed Sj25/TM4, has substantial amino acid homology to Sm23 from Schistosoma mansoni although it is not a species homologue of Sm23. Sj25/TM4 is predicted to span the cell membrane four times, with its NH2- and COOH-termini embedded in the cytoplasm, and to have two extracellular hydrophilic loops, one of which may be N-glycosylated. This topology is characteristic of TM4SF proteins; in addition, Sj25/TM4 contains the sequence motifs conserved in the TM4SF. Southern hybridization analysis demonstrated that Sj25/TM4 and Sj23 are encoded by genes at separate loci and, further, showed interstrain variation at the locus encoding Sj25/TM4 in Chinese and Philippine isolates of S. japonicum.