Objective: The effect of brief, prehypertensive therapy by angiotensin-converting enzyme inhibition (ACEi) with perindopril on the structure and function of large arteries was studied in rats. Methods: Spontaneously hypertensive rats (SHR) received perindopril (3mg/kg per day) between the ages of either 6 and 10 weeks (early) or 20 and 24 weeks (late) and compared with nonmedicated SHR and normotensive (Wistar-Kyoto) controls (n=6 per group). Haemodynamic parameters and segmental aortic stiffness assessed by pulse wave velocity (PWV) were measured under urethane anaesthesia [1.3g/kg, intraperitonealy (i.p.)] at 25 weeks. Aortic elastin and collagen content were determined by histomorphometry and calcium content by atomic absorption spectrophotometry. Results: Rats receiving brief, early perindopril therapy had lower tail-cuff SBP than nonmedicated SHR (121±1mmHg, 179±5mmHg, respectively, P<0.05), reflected in lower thoracic and abdominal aortic pulse pressures. Aortic pulse pressure amplification was lower with early perindopril treatment (early treated 10±5%, nonmedicated 20±10%, P<0.05). No blood pressure (BP) differences were observed between late treated and nonmedicated SHR. Isobaric thoracic PWV was lower when treated early but not later in life. Treatment did not alter abdominal PWV. Early treatment was associated with reduction in total aortic calcification (48%, P<0.001) and reduction in medial cross-sectional area (40%, P<0.05) of abdominal aorta compared with nonmedicated rats. Treatment increased the wall thickness/diameter ratio, but only early treated rats had a 46% higher elastin/collagen ratio compared with SHR controls. Conclusions: Early but not late brief ACEi decreased arterial pressure and isobaric wall stiffness in SHR. This was associated with marked alteration of wall structure and the effects persisted after cessation of early treatment. The structural mechanisms responsible for this change varied segmentally along the aortic trunk.