8 cirrhotics with hyponatremia were given demeclocycline (DMC) 900 mg/day to investigate its effect on renal function, plasma renin activity, aldosterone and urinary excretion of prostaglandin E<sub>2</sub> and kallikrein. In 7 patients DMC induced an increase of free water clearance (from – 0.36 ± 0.06 to 0.13 ± 0.06 ml/min) and serum sodium concentration (from 125.4 ± 0.09 to 131.1 ± 1.0 mEq/l, mmol/l). In 5 of these patients DMC also induced a marked reduction of glomerular filtration rate (from 72.2 ± 6.2 to 31,2 ± 4.7 ml/min) and renal plasma flow (from468 ± 98 to 195 ± 55 ml/min) which could not be explained on the basis of hypovolemia. In each case this renal impairment was not associated with changes in urinary concentration of β<sub>2</sub>-microglobulin, urinary casts excretion, fresh urine sediment or urine protein content and disappeared after discontinuation of the drug. DMC induced a marked increase in the urinary excretion of prostaglandin E<sub>2</sub> (from 0.82 ± 0.27 to 6.16 ± 1.91 ng/min) in 6 out of the 7 patients who responded to DMC and a marked reduction in urinary kallikrein (from 16.1 ± 4.4 to 4.2 ± 1.6 pkat/min) in the 5 patients who developed renal insufficiency. The serum DMC concentration was greater than 5 µg/ml in all patients who responded to DMC, greater than 8 µg/ml in all cases who developed renal insufficiency and of 3 µg/ml in the case not responding to DMC. These findings indicate that: (1) DMC is an effective therapy for water retention and dilutional hyponatremia in cirrhosis but it produces renal insufficiency associated with an impairment of renal perfusion and with a reduced urinary kallikrein activity in a high proportion of patients. (2) The inhibitory effect of DMC on water reabsorption in these patients may be due, at least in part, to an increased renal synthesis of prostaglandin E<sub>2</sub> induced by the drug. (3) A closed relationship exists between the renal effects and the serum levels of DMC in cirrhosis.