Left ventricular hypertrophy (LVH) is a dominant characteristic of cardiovascular mortality. We investigated the interaction between physical activity and LVH on stroke mortality, based on a 40-year follow-up of the Corfu cohort from the Seven Countries Study. The population studied consisted of 529 rural men (40-59 years old) enrolled in the Study at 1961. LVH was electrographically confirmed according to Minnesota coding. Physical activity levels were assessed by self-reports of habitual, occupational and leisure-time activities. Cox proportional hazard models were used to evaluate exercise levels with respect to stroke mortality in people with and without LVH. During the follow-up, 461 (87%) died, and 74 (16%) of these deaths were due to stroke. LVH was present in 40 (7.5%) men. A total of 362 (68%) men were defined as physically active. Physical activity was associated with a lower risk of stroke (hazard ratio=0.65, P<0.05). On the other hand, LVH had 5.8-fold the risk of stroke (P<0.001) among sedentary and 4.5-fold the risk (P<0.001) among physically active men, after controlling for several potential confounders. However, moderate physical activity decreased the risk of stroke by 49% in men with LVH as compared to sedentary without LVH (hazard ratio=0.51, P<0.01), while hard exercise did not confer any significant reduction in stroke risk. We revealed the benefits from moderate physical activity on stroke mortality among men with LVH. Physicians and other health-care professionals should encourage patients with LVH to adopt a physically active lifestyle.