The progression of renal disease depends on various clinical parameters such as hypertension and proteinuria. We recently showed that an increased renal resistance index measured by duplex ultrasound is associated with a poor prognosis in patients with renal artery stenosis. We now prospectively tested the hypothesis that a high renal resistance index (greater-than-or-equal 80) predicts progression of renal disease in patients without renal artery stenosis. In 162 patients newly diagnosed with renal disease, the resistance index (1-[end diastolic velocity/maximum systolic velocity]*100) was measured in segmental arteries of both kidneys. Creatinine clearance was measured at baseline, at 3, 6, and 12 months, and then at yearly intervals thereafter (mean follow-up 3 +/- 1.4 years). The combined endpoint was a decrease of creatinine clearance by greater-than-or-equal 50%, end-stage renal disease with replacement therapy, or death. Twenty-five patients (15%) had a renal resistance index value greater-than-or-equal 80 at baseline. Nineteen (76%) had a decline in renal function; 16 (64%) progressed to dialysis, and 6 (24%) died. In comparison, in patients with renal resistance index values <80, 13 (9%) had a decline in renal function, only 7 (5%) became dialysis-dependent, and 2 (1%) died (P<0.001). In a multivariate regression analysis, only proteinuria and resistance index were independent predictors of declining renal function. A renal resistance index value of greater-than-or-equal to 80 reliably identifies patients at risk for progressive renal disease.