Postprandial elevation of 5-phosphoribosyl 1-diphosphate (PPRibP) concentration in the mouse liver (Lalanne, M. and Henderson, J.F. (1975) Can. J. Biochem. 53,394-399) was further studied regarding the effects of protein intake and the underlying mechanisms. The extent and duration of the increase depended on the quantity and quality of proteins ingested. The order of effectiveness of various diets was as follows: 60% casein greater than 20% egg albumin greater than 20% casein greater than 20% gelatin = 20% gluten greater than 20% zein greater than 0% casein. Hepatic purine and pyrimidine biosyntheses de novo, as measured by labelled tracer incorporation, increased with increasing protein intake. Nicotinic acid incorporation into NAD increased equally, whether casein-containing or casein-free diets were given. Therefore, the increase of PPRibP level may be brought about by increase in its synthesis. Administration of glucagon or epinephrine similarly elevated the hepatic level of PPRibP. Somatostatin, known to inhibit secretion of pancreatic hormones, suppressed the casein-diet-dependent PPRibP level increase. Colchicine markedly inhibited the casein-diet- and glucagon-dependent responses, but not the epinephrine effect. It is likely that glucagon is a major factor in mediation of the protein-diet-dependent PPRibP level increase and that the cytoskeleton is involved in the glucagon-mediated response.