Ten patients, mean age 51.50±3.03 years, with degenerative rheumatism on NSAID treatment without any sign of renal desease, and 11 control subjects, mean age 43.50±1.51 years, were studied. NSAID treatment was of 11.30±5.60 weeks duration in average, with ibuprofen, naproxen, or indomethacin. Urinary excretion of three specific renal tubular enzymes—AAP: alanine-amino-peptidase, GGT:γ-glutamyl-transpeptidase, andβ-NAG:β-N-acetyl-glucosaminidase, were determined in 8-h overnight urine samples, as well as GFR creatinine clearancel 1.73 m2, urinary volume/8 h, specific gravity of the urine, proteinuria and glucosuria. In the group treated with NSAIDs, urinary excretion of the enzymes was significantly higher than in the control group—AAP: 1414.20±317.60, 864.20±94.42, p<0.00001; GGT: 8034.6±1378.55, 5095.64±614.40, p<0.00001, andβ-NAG: 1644.60±299.97, 964.82±142.00, p<0.00001. Patients on NSAID treatment showed abnormal urinary excretion of AAP in 7/10 cases, of GGT in 6/10, and ofβ-NAG in 7/10 cases. Duration of the treatment did not correlate with the urinary excretion of the enzymes. Age was in correlation with the urinary excretion of the enzymes only in the control group, r = 0.52, p<0.005 for AAP, r = -0.43, p<0.02 for GGT, and r = -0.23, p<0.05 forβ-NAG. Our results suggest that after long-term administration of NSAIDs, toxic renal tubular involvement is frequent, that urinary excretion of three specific renal tubular enzymes could be a suitable tracer of the toxic effects of the drugs at the cellular level, and that prolonged cellular injury could lead toward progressive renal damage, with a rather“silent”clinical picture.