The effect of meclofenamate on urinary protein excretion, level of serum albumin, and renal function was studied prospectively in 30 patients with corticosteroid-resistant severe nephrotic syndrome: 16 with focal segmental glomerulosclerosis, 12 with membranous glomerulopathy, and 2 with minimal-lesion nephropathy. Seventeen patients had a 40% or more reduction in urinary protein excretion ("responders"), and the decrease continued during long-term treatment. Meclofenamate therapy was discontinued after 2 months in eight "nonresponders" and in five other patients because of side effects (progressive increase in the level of serum creatinine in two, diarrhea in two, and pruritus in one). In responders, we recorded the following findings (mean +/- SD): urinary protein excretion decreased from 13.0 +/- 5.2 g/24 h to 7.2 +/- 3.5 g/24 h in 2 to 4 weeks and continued to decrease to 4.1 +/- 1.4 g/24 h at the time of the last follow-up study (median duration, 12 months; range, 6 to 36 months; P less than 0.01, 2 to 4 weeks versus later follow-up); the level of serum albumin increased from 1.9 +/- 0.5 g/dl to 2.9 +/- 0.7 g/dl (P less than 0.001) in 2 to 4 weeks; the level of serum cholesterol decreased from 413 +/- 125 mg/dl to 346 +/- 114 mg/dl (P less than 0.005) at the time of the last follow-up examination; and renal function remained unchanged from the baseline study to the follow-up study (serum creatinine 1.5 +/- 0.5 mg/dl versus 1.6 +/- 0.4 mg/dl and glomerular filtration rate 60.5 +/- 29.2 ml/min per 1.7 m2 versus 64.1 +/- 25.5 ml/min per 1.7 m2).(ABSTRACT TRUNCATED AT 250 WORDS)