Age-related macular degeneration (AMD) is characterized in part by the deposition of extracellular deposits, including drusen, in the aging macula. A number of clinical studies have revealed a strong association between the number, size, and degree of confluency of drusen and AMD. Although a number of distinct morphological classes, or phenotypes, of drusen can be resolved at the ultrastructural level, very little is known about the compositional and etiological relationship between these phenotypes. A number of recent studies have begun to provide insight into the composition of drusen at the light microscopic level of resolution. Out of 33 extracellular matrix proteins evaluated, vitronectin was identified in hard and soft drusen [FASEB J 1999; 13:477-84]. Drusen have also been found to contain carbohydrate moieties which are labeled by wheat germ agglutinin (WGA), and Limax flavus agglutinin (LFA). We have recently extended these histochemical, immunohistochemical, and biochemical investigations to examine the relationship between substructural drusen phenotype and composition. The initial results of these observations, generated from a repository of human donor eyes processed within four hours of death, are reported herein. Five distinct substructural drusen phenotypes were identified in tissue sections from eyes of approximately 400 donors; all five phenotypes were observed in eyes from donors with and without clinically documented AMD. Interestingly, no strict relationship between size (one important discriminator between "hard" and "soft" drusen class) and morphology was noted for four out of the five drusen phenotypes. Sections from the same donors were incubated with antibodies directed against vitronectin and with the lectins WGA and LFA, three probes recently shown to label hard and soft drusen at the light microscopic level of resolution. As anticipated, all of these probes bound to all phenotypes of drusen examined. These data suggest that different phenotypes of drusen, although they may differ significantly with respect to their substructural morphology, may possess a similar complement of extracellular matrix-associated proteins and saccharides. Ongoing investigations are directed toward determining whether there exist specific drusen constituents, not yet identified, that impart phenotypic and/or ontogenic specificity to drusen. It is anticipated that a more complete understanding of drusen composition, as it relates to phenotype, will provide significant new insight into the biology and etiology of various clinically manifested forms of AMD.