An immunological investigation was conducted of soluble intra‐crystalline macromolecules isolated from living and fossil brachiopod shells, which had previously been used for an immunologically based study of phylogeny (serotaxonomy). The soluble intra‐crystalline macromolecules comprised 0.03% by weight of the extant shell material. Bulk analysis and gel electrophoresis indicated that the organic material is predominantly glycoprotein, and contains up to 30% by weight carbohydrate. Treatment of the macromolecules with periodate and proteinase K revealed that antibodies were raised predominantly against the carbohydrate moieties. Using a specially adapted dot blot immunobinding assay (DIBA) the decay in immunological signal over geological time was determined. Pleistocene shells have lost between 99 and 99.9% of immunological reactivity, and original antigenic determinants form a declining proportion of total organic matter. It is suggested that condensation reactions between amino acids and sugars account for the rapid destruction of determinants; this has important implications for the direction of future studies on fossil macromolecules. □Serotaxonomy, biomolecular palaeontology, glycoproteins, melanoidins, brachiopods.