Nitric oxide exerts multiple effects on renal function. It remains unclear whether endogenous nitric oxide production is increased or decreased in patients with chronic renal failure. To evaluate endogenous nitric oxide production in these patients we studied exhaled nitric oxide output by an ozone chemiluminescence method and plasma NO2-/NO3- levels by the Griess method in 40 patients with end-stage chronic renal failure who underwent regular continuous ambulatory peritoneal dialysis (n = 30) or haemodialysis (n = 10), and in 28 healthy subjects. Patients with chronic renal failure had a higher exhaled nitric oxide concentration [39±3 versus 19±1 parts per billion, (mean±S.E.M.), P< 0.0001], a greater nitric oxide output (177±11 versus 96±7 ;nl·min-1·m-2, P< 0.001) and a higher plasma NO2-/NO3- concentration (96±14 versus 33±4 ;μmol, P< 0.01) than controls. These values did not differ between patients on haemodialysis and those on continuous ambulatory peritoneal dialysis. Patients with chronic renal failure had significantly higher plasma concentrations of both interleukin-1β and interferon-γ than controls. The exhaled nitric oxide output did not correlate with plasma NO2-/NO3- or with peritoneal dialysate NO2-/NO3-, but plasma NO2-/NO3- correlated with dialysate NO2-/NO3- in patients who underwent continuous ambulatory peritoneal dialysis (r = 0.77, P< 0.01). Haemodialysis for 4 ;h acutely decreased plasma NO2-/NO3- (92±17 versus 50±8 ;μmol, P< 0.05) and cGMP concentration (16.5±4.3 versus 5.1±1.7 ;pmol/ml, P< 0.01), but did not decrease exhaled nitric oxide output. The increase in exhaled nitric oxide with the simultaneous increase in circulating cytokines suggests that nitric oxide synthase seems to be induced significantly in patients with chronic renal failure. Increased endogenous nitric oxide production may have a pathophysiological role in patients with uraemia.