The aim of this study was to assess the effect of the angiotensin II receptor blocker Irbesartan on protein damage by glycation, oxidation and nitration in patients with type 2 diabetes and microalbuminuria. In a doublemasked randomised crossover trial of 52 hypertensive type 2 diabetic patients, antihypertensive treatment was replaced with bendroflumethiazide. After 2-months washout, patients were treated randomly with Irbesartan 300, 600, and 900 mg o.d., each dose for 2 months in a threeway crossover study. Glycation, oxidation and nitration adduct residues in plasma protein and related urinary free adducts were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Treatment with Irbesartan decreased urinary excretion of advanced glycation endproducts (AGEs)-methylglyoxaland glyoxal-derived hydroimidazolones, MG-H1 and G-H1. Urinary AGEs were decreased by 30-32%. In plasma protein, treatment with Irbesartan increased content of glycation adducts N ε-fructosyl- lysine, AGEs N ε-carboxymethyl- lysine, N ε- carboxyethyl-lysine and pentosidine, and also increased content of oxidation markers N-formylkynurenine and dityrosine. This was attributed to decreased clearance of plasma protein modified by Ne-fructosyl-lysine and oxidative markers through the glomerular filter tightened by Irbesartan treatment. Treatment of patients with type 2 diabetes with Irbesartan decreased urinary excretion of MG-H1, G-H1 and 3-NT, which may result from decreased exposure to these AGEs. This is likely achieved by blocking angiotensin II signalling and related down-regulation of glyoxalase 1 and may contribute to health benefits of Irbesartan therapy.