Abstract Objectives Previous studies have shown that biomarkers in blood plasma can predict bleeding complications during anticoagulant treatment as well as thromboembolic events and may improve existing risk stratification schemes in patients on or considered for oral anticoagulant treatment. The aim of this study was to investigate if levels of d-dimer, tissue plasminogen activator (tPA) and its complex with plasminogen inhibitor type 1 (tPA/PAI-1 complex) can predict major bleedings, cardiovascular events and all-cause mortality in patients with warfarin treatment. Design and methods In a longitudinal cohort study, 719 patients on oral anticoagulant treatment were followed for a total of 3001 treatment years. Major bleeding, stroke, arterial emboli, myocardial infarction and death were recorded and classified. Blood samples collected at baseline were analyzed for d-dimer, tPA, and tPA/PAI-1 complex. Results In multivariate Cox regression analysis, high levels of d-dimer were associated with major bleeding (HR 1.27 per SD; 95% CI: 1.01–1.60), cardiovascular events (HR 1.23 per SD; 95% CI: 1.05–1.45) and all-cause mortality (HR 1.25 per SD; 95% CI: 1.06–1.47). Neither tPA nor the tPA/PAI-1 complex was associated with major bleeding, cardiovascular events or all-cause mortality. Conclusion We conclude that high levels of d-dimer predict major bleeding, cardiovascular events and all-cause mortality during warfarin treatment.