Fasting hyperbilirubinemia (FHB) has previously been shown to be rapidly reversed by the ingestion of a mixed diet. This study examines the effect of carbohydrate, fat, amino acids, and noncaloric materials on FHB. After an initial fast of 15 to 39 hr, caloric and noncaloric materials were administered by mouth or vein to 13 subjects, and the total serum bilirubin (TSB) was determined frequently for 4.5 hr. Only oral glucose reversed FHB; the TSB did not change significantly from control studies after oral saline, mannitol, amino acids, and fat. In contrast, intravenous infusion of glucose resulted in a significant increase in TSB which could not be explained by osmotic or intravascular volume changes, and was nonspecific, since similar effects resulted from infusions of mannitol and amino acids. The results of this study demonstrate that oral glucose reverses FHB, and that under the conditions of these experiments other nutrients and noncaloric materials are ineffective. In contrast, intravenous glucose, mannitol, and amino acids increase the TSB by unknown mechanisms.