Objective: We investigated if the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to irbesartan, and the effect of the combination. Research Design and Methods: Double-blind, randomized, cross-over trial. After a one-month washout period 26 patients with type 2 diabetes, hypertension and albuminuria (>100mg/day) were randomized to four 2-month treatment periods in random order with placebo, aliskiren 300 mg once daily, irbesartan 300 mg once daily or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. Primary endpoint was change in albuminuria. Secondary measures included change in 24h blood pressure (24h BP) and glomerular filtration rate (GFR). Results: Placebo geometric mean albuminuria was 258 mg/day (range 84-2361), mean 24h BP was 140/73 (SD 15/8) mmHg, GFR was 89 (SD 27) ml/min/1.73 m(2). Aliskiren treatment reduced albuminuria by 48% (95% confidence interval 27-62) compared to placebo (p<0.001), not significantly different from irbesartan treatment (58% (42-70) (p<0.001 vs. placebo)). Combination treatment reduced albuminuria by 71% (59-79), more than either monotherapy (p<0.001 and p=0.028). Fractional clearances of albumin were significantly reduced (46, 56 and 67% reduction vs. placebo). 24h BP was reduced 3/4 mmHg by aliskiren (NS/p=0.009), 12/5 mmHg by irbesartan (p<0.001/p=0.002) and 10/6 mmHg by the combination (p=0.001/p<0.001). GFR was significantly reduced 4.6 (0.3, 8.8) ml/min/1.73m(2) by aliskiren, 8.0 (3.6, 12.3) ml/min/1.73m(2) by irbesartan and 11.7 (7.4, 15.9) ml/min/1.73m(2) by the combination. Conclusions: Combining aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria as compared to monotherapy.