Importance: Response to warfarin is influenced by a multitude of patient-specific factors including genetics, clinical comorbidities, and concomitant medications. Objective: To determine the influence of consistent physical activity on stable warfarin dose (mg/day), anticoagulation control (percent-time-in-target-range; PTTR) and risk of major hemorrhage among patients on chronic anticoagulation therapy. Methods: Physical activity was ascertained by self-report at initiation of warfarin therapy (target INR=2-3) in 1276 patients with changes documented at monthly anticoagulation clinic visits. The association of consistent physical activity (maintained over >80% of visits) on warfarin response and anticoagulation control was evaluated using multi-variable linear regression analysis and for major hemorrhage using survival analysis. Results: The number of participants who were consistently physically active (>30 minutes >3 times/week) were 683 (53.7%). Physically active patients required 6.9% higher warfarin doses (p=0.006) and achieved better, although not statistically significant, anticoagulation control (50% vs. 48%; p=0.13) with fewer clinic visits (1.9 vs. 2.5 per patient/ month; p<0.0001) compared to physically inactive patients after accounting for demographic, clinical and genetic factors. There were 137 major hemorrhagic events encountered over 1801 person years of follow-up (incidence 7.6/100pyrs; 95% CI: 6.4 -8.9). The incidence of hemorrhage was lower among physically active patients (5.6/100pyrs; 95% CI: 4.2-7.2) compared to inactive patients (10.3/100 pyrs; 95% CI: 8.2-12.9; p=0.0004). Active patients had a 38% lower risk of hemorrhage (HR: 0.62, 95% CI: 0.42-0.98, p= 0.03) compared to inactive patients after adjusting for bleeding risk (HAS-BLED score), clinical and genetic factors. Conclusion and Relevance: Consistent physical activity is associated with higher warfarin dose requirements but with improved anticoagulation control and lower risk of hemorrhage. In addition to the beneficial effects of physical activity to health and longevity, its influence on drug response needs to be better understood and the mechanisms through which physical activity exerts these effects need to be elucidated.