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Dual pathway inhibition (DPI) with low dose rivaroxaban and aspirin in patients with coronary artery (CAD) and/or peripheral artery disease (PAD) reduces the occurrence of cardiovascular (CV) events; however, the underlying mechanisms explaining these latter CV benefits are not clearly understood. Our explorative observational study aimed to evaluate the effect of DPI on plasma inflammation and coagulation markers among real-world patients with CAD and/or PAD. We prospectively included all consecutive patients with an established diagnosis of CAD and/or PAD treated with aspirin (ASA) 100 mg once daily (OD) and rivaroxaban 2.5 mg twice daily (TD). Clinical evaluation and laboratory analyses, including haemoglobin, renal function (creatinine, urea, cystatin-C); coagulation markers (INR, aPTT); inflammation markers (IL-6, CRP, lipoprotein-associated phospholipase A2, copeptin), growth differentiation factor-15 (GDF-15), were carried-out at baseline, before starting treatment, and at 4 and 24 weeks after study drugs administration. 54 consecutive patients (mean age 66 ± 7 years; male 83%) who completed the six-months follow-up were included. At 24 weeks follow-up, a statistically significant reduction in IL-6 serum levels (4.6 [3.5- 6.5] vs 3.4 [2.4- 4.3] pg/ml; p=0.0001) and fibrinogen (336 [290- 390] vs 310 [275- 364] mg/dl; P=0.04) was shown; moreover, a significant increase in GDF-15 serum level (1309 [974- 1961] vs 1538 [1286- 2913] pg/ml; p=0.002) was observed. Haemoglobin, renal function and cardiovascular homeostasis biomarkers remain stable over the time. The anti-Xa activity at both (0.005 [0-0.02] vs 0.2 [0.1-0.34]; p