In human serum, at least two molecular species of the neural cell adhesion molecule (NCAM) with molecular weights of 110,000–130,000 and 150,000–180,000, respectively, can be identified by Western blotting. Both are characterized by the absence of epitopes for monoclonal antibodies KD11 and MG5, which specifically recognize intracellular domains of the human NCAM transmembrane isoforms, NCAM-140 and NCAM-180. In contrast to the Mr 110,000–130,000 molecule also detectable in serum samples from healthy blood donors, the Mr 150,000–180,000 molecule appears to be tumor associated. The only difference between these two species is shown to be the presence of long chains of α-(2,8)-linked N-acetylneuraminic acids, which are characteristic for the so-called embryonic NCAM form. After treatment with endoneuraminidase N, the Mr 150,000–180,000 molecule can no longer be discriminated from the Mr 110,000–130,000 molecule in Western blotting as well as gel and anion exchange chromatography experiments. The experimental data clearly show that only the embryonic NCAM molecule carrying the poly-α-(2,8)-linked N-acetylneuraminic acid moiety can be regarded as a specific serum marker for small cell lung cancer.