The ability of the kidney to synthesize urea is of interest and some controversy. We tested the hypothesis that low plasma urea concentrations would stimulate renal urea synthesis, thereby enhancing urinary concentrating ability. We defined a ratio of specific activity of plasma/specific activity of urine (SA ratio) greater than 1.0 as indicative of de novo intrarenal urea synthesis. We studied dogs on 3 dietary regimens: (1) commercial chow ad libitum; (2) restricted rations of the same chow; (3) protein-free diet ad libitum with vitamin/mineral supplement. A significant inverse relationship between plasma urea concentration and SA ratio was seen only in the ration-restricted group, despite the fact that plasma urea concentrations in this group were highest of the three groups. In addition, dogs in this group were more likely to demonstrate renal urea synthesis than dogs in the other groups. Thus, the dog kidney is capable of de novo urea synthesis, but a reduced plasma urea concentration does not necessarily stimulate this metabolic activity. Other factors in addition to the plasma urea concentration appear to be involved in the regulation of renal urea synthesis.