Background: Tyrosine kinase inhibitors (TKIs) of vascular endothelial growth factor receptor (VEGFR) may interfere with the coagulation system making patients susceptible to both hemorrhage and thromboembolism. Some cancer patients require dual treatment with VEGFR TKIs and factor Xa inhibitors. However, the safety of such combination treatment (e.g. bleeding risk) has not been well characterized in the literature. Methods: This retrospective study identified metastatic cancer patients who received VEGFR TKIs (pazopanib, sunitinib, sorafenib, axitinib, regorafenib, vandetanib, lenvatinib, cabozantinib, tivozanib) and Xa inhibitors (low-molecular weight heparin [LMWH] or direct oral anticoagulants [DOACs]- rivaroxaban or apixaban) from 2001 to 2018 at the Ohio State University. We assessed bleeding risks of dual therapy vs factor Xa inhibitors alone, using the same patients as self-controls. We defined bleeding based on criteria from the International Society on Thrombosis and Haemostasis. Fisher’s exact test was used to compare distribution of bleeding severities and the Cox model was used to analyze bleeding risk. Results: A total of 86 patients were included for analysis, with a median age of 56 (range, 34-88). The patient population was predominantly of male gender (69.7%), Caucasian race (89.3%) and renal cell cancer type (48.9%). As some patients had been on both LMWH and DOAC at different time periods, we found that 81 patients received concurrent TKI and LMWH; 19 patients had concurrent TKI and DOAC. Overall, 25 patients developed 29 clinically significant bleeding events (including 8 major bleeding) during concurrent treatment, and 15 patients developed 17 clinically significant bleeding events (4 major bleeding) during factor Xa inhibitor alone over a median follow up of 63 days. We found a statistically higher bleeding risk with concurrent treatment (HR = 2.23, 95% CI, 1.13–4.42, p = 0.02) compared with Xa inhibitor alone. In a stratified analysis, concurrent VEGFR TKI plus LMWH or DOAC both showed a strong trend for elevated bleeding risk. Although there were increased bleeding events with concurrent treatment, there was no significant difference in the proportion of major bleeding (27.6% vs 23.5%, p = 0.76). Median time to first bleeding event was 56 days for concurrent therapy and 72 days for Xa inhibitor alone. Conclusions: Concurrent treatment of VEGFR TKI and factor Xa inhibitors is associated with significantly increased bleeding risk when compared with factor Xa inhibitors alone in metastatic cancer patients.