Objective: Evaluation of the benefit/risk ratio of long-term treatment with indomethacin in salt-losing tubulopathies with special attention to renal function. Study design: Twelve patients (median age, 14.9 years) had received indomethacin for a median of 13 years (median cumulative dose, 10.7 g/kg). Creatinine clearance, serum electrolyte levels, endocrine status, and excretion of prostaglandins and electrolytes were examined during indomethacin therapy and after its withdrawal. All patients underwent ultrasound-guided renal biopsy. For statistical evaluation, the Wilcoxon test and Pearson correlation coefficient were used. Results: After indomethacin withdrawal, the biochemical features of the tubulopathy reappeared. The median creatinine clearance rose from 67.4 to 96.5 mL/min/1.73 m² (P < .05) but remained subnormal in 4 patients. Ultrasonography elucidated medullary nephrocalcinosis in 8 patients. Renal tissue showed slight/moderate focal tubular atrophy and interstitial fibrosis in 8 patients. Comparison with biopsy specimens, obtained 11 to 14 years before study participation from 5 patients, revealed no progression. A correlation between fractional sodium and magnesium excretion and percentage of altered tubulointerstitial compartment was found (P < .001). The 4 patients with mutations in the gene of the inwardly rectifying adenosine triphosphate–regulated potassium channel (ROMK) had almost normal renal histologic findings and normal renal function. Conclusion: Renal function and histology are unaffected by long-term indomethacin treatment. (J Pediatr 2001;139:398-406)