The case of a 43-old-year woman who had a generalized asymptomatic pigmentary disorder with onset at about age 20 is presented. Tracing back her family history, we found that her father and six of her siblings had also suffered a similar skin pigmentary defect with onset at the same approximate age. In depigmented lesions, three distinct histopathological features were observed: (1) decreased epidermal melanin content and lower density of melanocytes in the upper dermis; and (3) ultrastructural vacuolar degeneration in the focal melanocytes and in the keratinocytes immediately nearby. No deposit of amyloid was observed in the biopsied skin specimens. In hyperpigmented lesions, the histopathological features included: (1) increased melanin content and high density of melanocytes; (2) few melanophages in the papillary dermis of focal areas, but no vacuolar degeneration of the epidermal cells; and (3) an increased number of melanosomes in the basal and suprabasal keratinocytes. Direct immunofluorescence examination revealed no deposit of immunoglobulins in either the hyperpigmented or depigmented lesions. By indirect immunofluorescence examination, the serum of the patient was found to contain antinuclear antibodies (ANA, IgG, class, homogeneous pattern); however, the maximal positive dilution titer of sera against cultured human cells was much higher in melanocytes (1:500 dilution) than in keratinocytes (1:50 dilution) or fibroblasts (1:10 dilution). The pathogenesis of dyschormatosis universalis hereditaria remains unclear; however, hereditary genetic defects may play an important role in alternating regular melanogenesis, which results in a pigmentary anomaly.