Vitamin K antagonists (VKAs) remain one of the most commonly used anticoagulation therapies. The potential anticancer effect of long-term use of VKAs has been a matter of debate with conflicting results. Our goal was to perform a systematic review and meta-analysis examining the association between long-term VKAs use and cancer risk.Systematic searches of multiple major databases were performed from inception until January 2018. We included studies of adults that compared incidence of any cancer between ≥6 months use of VKAs (long-term group) and <6 months use of VKAs or nonuse (control group). Primary outcome was all-cancer incidence and secondary outcomes were cancer-specific incidence, all-cause death and cancer-specific mortality. Hazard ratios (HRs) were pooled using a random-effects model, and individual studies were weighted using inverse variance.We identified 9 observational studies that included 1,521,408 patients. No randomized trials were identified. In comparison to control, long-term use of VKAs was associated with a significant reduction in incidence of all cancers (HR, 0.84; 95% confidence interval [CI], 0.81-0.88; P<0.001). In a prespecified subgroup analysis, long-term use of VKAs demonstrated a significant reduction in all-cancer incidence when compared with control in individuals whose indication for VKAs were venous thromboembolism (HR, 0.69; 95% CI, 0.52-0.90; P=0.007).The use of long-term VKAs, for any indication, is associated with lower cancer incidence. This finding could have important clinical implications for the choice of oral anticoagulation therapies among specific patients with a higher baseline risk of cancer.