The mechanism of action of lactulose is not known, although in vitro evidence suggests that lactulose may increase ammonia utilization and decrease ammmonia production by gut flora. If these changes occur in patients, they should be reflected in altered urea metabolism and nitrogen excretion. In seven studies conducted in 6 cirrhotic patients, the effects of lactulose on the kinetics of urea metabolism and nitrogen excretion were determined. Lactulose caused a fall in urea production (-24%, P less than 0.005) that was reflected in a decrease in both urea degradation and urinary urea excretion. Likewise, lactulose caused a decrease in the total body urea pool. The fall in urinary urea was accompanied by a large (two- to threefold) increase in stool nitrogen that was of a similar magnitude of the fall in urinary urea. Although urea degradation fell after lactulose, the intestinal (extrarenal) clearance of urea did not, indicating that the fall in urea degradation was due to the observed fall in the urea pool. The results indicate that: (a) Lactulose decreases urea production by increasing the fecal output of nitrogen, a finding compatible with altered ammonia metabolism by gut flora. (b) Lactulose decreases urea degradation, although this effect is primarily the result of a fall in the urea pool and cannot be attributed to an inhibition of urea breakdown in the gut lumen.