Introduction: Physical activity amplifies respiratory uptake and deposition of air pollutants in the lung, which may augment acute harmful effects of air pollution during exercise. We aimed to examine whether long-term benefits of physical activity on morbidity and mortality are moderated by long-term exposure to air pollution levels in an urban setting.Methods: 57,000 subjects (50–65 years) from the Danish Diet, Cancer, and Health cohort, were recruited in Aarhus and Copenhagen between 1993 and 1999, when they reported data on lesiure-time and utilatarian physical activity. We linked the cohort to Danish natiowide registers to extract data on overall- and cause-specific mortality, incidence of asthma and chronic obstructive pulmonary disease (COPD), and incidence of myocardial infarction (MI) and stroke. We used modeled NO2 levels (high/medium/low) at the residence at the cohort baseline year as proxy for air pollution exposure during physical activity. We modeled assocaition of participation in sports, cycling, gardening, and walking with the above mentioned health outcomes by Cox regression, and introduced NO2 (low/medium/high) as an interaction term.Results: Of ca. 53,000 subjects, 5,534 died until 2010, 1,151 developed asthma and 3,225 COPD until 2013, 2,936 developed MI and 4,353 stroke until 2015. Participation in sports, cycling, walking and gardening was associated with reduced risk of premature mortality (18-22%), as well as with incident asthma (15-18%), COPD (15-19%), MI (9-15%), and stroke (10-18%), and these were not modified by NO2.Conclusions: Increased exposure to air pollution during exercise in urban setting does not outweigh beneficial effects of physical activity on the risk of premature mortality, respiratory and cardiovascular morbidity.