Serum prealbumin and retinol binding protein (RBP) concentrations were determined for 68 members of a kindred in Indiana with a familial type of systemic amyloidosis. Immunohistochemical studies on rectal and muscle biopsy material from individuals with this type of amyloidosis revealed staining of amyloid deposits with anti-prealbumin. Both the serum prealbumin and RBP concentrations were significantly depressed in 9 patients with amyloidosis when compared with normal controls and unaffected kin. In addition, the mean RBP serum concentration of 21 offspring of the patients with amyloidosis was significantly depressed. A more significant finding was that on the basis of the serum RBP concentrations, the offspring could be divided into 2 distinct groups. One group represented approximately 50% of the children and had serum prealbumin and RBP concentrations not significantly different from their afflicted parents. The second group had serum prealbumin and RBP concentrations not significantly different from those of normal controls and non-affected kin. These findings show that prealbumin and RBP serum concentrations are depressed in patients with the Indiana type of hereditary amyloidosis and that these serum abnormalities may be present long before development of clinical disease. They suggest that individuals with this genetic abnormality may be identified prior to clinical expression of the disease.