1. Renal specific targeting of the non-steroidal anti-inflammatory drug naproxen was obtained by coupling to the low-molecular-mass protein lysozyme. A previous study showed that conjugation to lysozyme resulted in a 70-fold increase of naproxen accumulation in the kidney with a subsequent renal release of the active metabolite naproxen–lysine. 2. In the present study we questioned whether naproxen–lysozyme is active in the rat kidney, inhibiting the urinary excretion of prostaglandin E 2 and renal sodium and water excretion in salt-restricted baseline conditions as well as during frusemide treatment. 3. A high dose of free naproxen (10 ;mg·day -1 ·kg -1 ) did not affect prostaglandin E 2 excretion in baseline conditions (naproxen, 11±1 ;ng/8 ;h; vehicle, 13±4 ;ng/8 ;h), whereas sodium and water excretion were, respectively, 3.0 and 1.6 times lower in the naproxen group ( P < 0.05). Naproxen completely prevented the frusemide-induced increase (3-fold) in prostaglandin E 2 excretion (naproxen 6.6±1.1 ;ng/8 ;h, vehicle 40±12 ;ng/8 ;h, P < 0.005). Frusemide-stimulated natriuresis and diuresis were, respectively, 1.6 ( P < 0.05) and 1.8 times ( P < 0.005) lower in the naproxen group. 4. A dose of 2 ;mg·day -1 ·kg -1 lysozyme-conjugated naproxen did not affect prostaglandin E 2 excretion in baseline conditions (conjugate, 18±2 ;ng/8 ;h; vehicle, 24±5 ;ng/8 ;h). The conjugate also had no effect on sodium and water excretion. However, the naproxen conjugate completely prevented the frusemide-induced increase (2-fold) in prostaglandin E 2 excretion (conjugate, 16±3 ;ng/8 ;h; vehicle, 48±13 ;ng/8 ;h, P < 0.05). Surprisingly, frusemide-induced natriuresis and diuresis were not affected by the conjugate. 5. In conclusion, a renal specific delivery of the non-steroidal anti-inflammatory drug naproxen using lysozyme results in an inhibitory effect on renal prostaglandin E 2 synthesis but does not affect the excretion of sodium and water, in contrast to free naproxen.