To study the impact of resting heart rate and leisure time physical activity at middle age on long term risk of drug treated lone atrial fibrillation (AF). Longitudinal cohort study of 309 540 Norwegian men and women aged 40-45 years examined during 1985-1999 followed from 2005 through 2009. Data from a national health screening programme were linked to the Norwegian Prescription Database (NorPD). The cohort comprised 162 078 women and 147 462 men; 575 (0.4%) men and 288 women (0.2%) received flecainide and 568 men and 256 women sotalol and were defined as patients with AF. No interventions. The outcome was lone fibrillation defined by having at least one prescription of flecainide or sotalol registered in NorPD between 2005 and 2009. Cox proportional hazard regression models were used to assess time to first prescription. The risk for being prescribed these drugs increased with decreasing baseline resting heart. Adjusted hazard ratio (HR) per 10 beats/min decrease in resting heart rate for flecainide prescription was 1.26 in men (95% CI 1.17 to 1.35) and 1.15 (95% CI 1.05 to 1.27) in women. Similar effects were seen for sotalol in men, but not in women. Men who reported intensive physical activity were more often prescribed flecainide than those in the sedentary group (adjusted HR=3.14, 95% CI 2.17 to 4.54). This population based study supports the hypothesis that the risk of drug treated lone AF increases with declining resting heart rate in both sexes, and with increasing levels of self-reported physical activity in men.