We investigated the role of the angiotensinogen (AGT) gene M235T polymorphism in determining blood pressure (BP) response to moderate intensity exercise in a 6-yr randomized controlled trial in 140 middle-aged men. Sitting, supine, and standing blood pressures were measured annually. Of the randomized men, 86% participated in the trial for 6 yr. Submaximal cardiorespiratory fitness increased by 16% in the exercise group. In the M homozygotes, sitting systolic BP decreased by 1.0 mmHg in the exercise but increased by 14.6 mmHg in the reference group (P = 0.007 for net effect). Sitting and supine diastolic BP decreased by 6.2 and 3.3 mmHg in the exercise but increased by 2.8 and 3.2 mmHg in the reference group (P = 0.026 and 0.024 for net effects), respectively. Regular moderate intensity exercise attenuates aging-related increase in systolic BP and decreases diastolic BP among the M homozygotes of the AGT gene M235T polymorphism.