Background: Over the past several decades, numerous large cohort studies have attempted to quantify the protective effect of physical activity on cardiovascular and all-cause mortality. The aim of the authors' review was to provide an up-to-date overview of the study results. Methods: In a systematic MEDLINE search conducted in May 2007, the authors included cohort studies that assessed the primary preventive impact of physical activity on all-cause and cardiovascular mortality. The authors reported risk reductions on the basis of comparison between the least active and the most active population subgroups, with the least active population subgroup as the reference group. Random-effect models were used for meta-analysis. Results: A total of 33 studies with 883,372 participants were included. Follow-up ranged from 4 years to over 20 years. The majority of studies reported significant risk reductions for physically active participants. Concerning cardiovascular mortality, physical activity was associated with a risk reduction of 35% (95% confidence interval, 30-40%). All-cause mortality was reduced by 33% (95% confidence interval, 28-37%). Studies that used patient questionnaires to assess physical activity reported lower risk reductions than studies that used more objective measures of fitness. Conclusions: Physical activity is associated with a marked decrease in cardiovascular and all-cause mortality in both men and women, even after adjusting for other relevant risk factors.