The results of postmortem examinations in four I-cell disease (ICD) patients, 2 weeks, 8.5 months, 4 and 10 years of age, respectively, are compared and evaluated. The most characteristic histological feature in ICD is the storage of membrane-bound vacuoles with fibrillo-granular contents in fibroblasts and of smaller inclusions with concentric ring-like profiles in endothelial cells. In older patients only, more heterogeneous cell inclusions with osmiophilic lamellar profiles may be found. The morphological lesions in the central nervous system (CNS) are hardly significant. Obvious abnormalities are present in the heart valves of even the very young patients, while alterations in the renal glomeruli are less severe in the long surviving patient. This difference may be viewed as histological confirmation of the proved genetic heterogeneity in ICD. The paradox of cell type-specific morphological findings on the one hand and the generalized deficiency of N-acetylglucosamine-1-phosphotransferase representing the primordial enzyme deficiency in ICD on the other, is resolved by postulating, outside the mannose-6-phosphate recognition marker targeting system, the existence of alternative mechanisms for distribution and processing of lysosomal enzymes in cells other than fibroblasts or endothelial cells.