OBJECTIVE - Ruboxistaurin selectively inhibits protein kinase C-β and ameliorates kidney disease in animal models of diabetes. The purpose of this study was to evaluate the effects of ruboxistaurin on diabetic nephropathy in humans. RESEARCH DESIGN AND METHODS - A randomized, double-blind, placebocontrolled, multicenter, pilot study was performed to evaluate the effects of 32 mg/day ruboxistaurin for 1 year in persons (n = 123) with type 2 diabetes and persistent albuminuria (albumin-to-creatinine ratio [ACR] 200-2,000 mg/g), despite therapy with renin-angiotensin system inhibitors. The primary end point was a change in the ACR. Estimated glomerular filtration rate (eGFR) (four-component equation from the Modification of Diet in Renal Disease study) was also calculated. RESULTS - At baseline, urinary ACR was 764 ± 427 mg/g (means ± SD), and eGFR was 70 ± 24 ml/min per 1.73 m 2. Systolic and diastolic blood pressures were 135 ± 14 and 75 ± 9 mmHg, respectively. HbA1c was 8.0 ± 1.2%. After 1 year, urinary ACR decreased significantly (-24 ± 9%) in participants treated with ruboxistaurin (P = 0.020) and nonsignificantly (-9 ± 11%) in the placebo group (P = 0.430). The ACR-lowering effect of ruboxistaurin appeared by 1 month. eGFR did not decline significantly in the ruboxistaurin group (-2.5 ± 1.9 ml/min per 1.73 m2) (P = 0.185), whereas the placebo group lost significant eGFR over 1 year (-4.8 ± 1.8 ml/min per 1.73 m2) (P = 0.009). Between-group differences for changes in ACR and eGFR were not statistically significant, but this pilot study was underpowered to determine such differences. CONCLUSIONS - In persons with type 2 diabetes and nephropathy, treatment with ruboxistaurin reduced albuminuria and maintained eGFR over 1 year. Ruboxistaurin may add benefit to established therapies for diabetic nephropathy.