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Background: Hemodialysis (HD) per se is a risk factor for thrombosis. Considering the growing body of evidence on blood-flow restriction (BFR) exercise in HD patients, identification of possible risk factors related to the prothrombotic agent D-dimer is required for the safety and feasibility of this training model. The aim of the present study was to identify risk factors associated with higher D-dimer levels and to determine the acute effect of resistance exercise (RE) with BFR on this molecule. Methods: Two hundred and six HD patients volunteered for this study (all with a glomerular filtration rate of <15 mL/min/1.73 m2). The RE + BFR session consisted of 50% arterial occlusion pressure during 50 min sessions of HD (intradialytic exercise). RE repetitions included concentric and eccentric lifting phases (each lasting 2 s) and were supervised by a strength and conditioning specialist. Results: Several variables were associated with elevated levels of D-dimer, including higher blood glucose, citrate use, recent cardiovascular events, recent intercurrents, higher inflammatory status, catheter as vascular access, older patients (>70 years old), and HD vintage. Furthermore, RE + BFR significantly increases D-dimer after 4 h. Patients with borderline baseline D-dimer levels (400–490 ng/mL) displayed increased risk of elevating D-dimer over the normal range (≥500 ng/mL). Conclusion: These results identified factors associated with a heightened prothrombotic state and may assist in the screening process for HD patients who wish to undergo RE + BFR. D-dimer and/or other fibrinolysis factors should be assessed at baseline and throughout the protocol as a precautionary measure to maximize safety during RE + BFR.