Background <p>Deep vein thrombosis (DVT) is a prevalent complication associated with malignancy. Clinical use of thromboprophylaxis is recommended, however its usage is limited due to bleeding complications, more cost associated, and reluctance to receive anticoagulant injections. Rivaroxaban a relatively easy to administer anticoagulant but it has a risk of bleeding and is expensive. Inflammation is the important factor in pathogenesis of cancer-associated thrombosis. Statins have the anti-inflammatory property that could decrease proinflammatory cytokines. Consequently, statins may be used as thromboprophylaxis for cancer patients receiving chemotherapy.</p> Objective <p>To provide comparison between atorvastatin and rivaroxaban on affecting inflammatory biomarkers (interleukin 6 [IL-6], C reactive protein [CRP]) and coagulation activation biomarkers (Tissue Factor [TF], prothrombin fragment 1 + 2 [F1 + 2], D-Dimer) in cancer patients at high risk of thrombosis receiving chemotherapy.</p> Methods <p>A randomized controlled study that was double-blinded and involved high-risk cancer patients undergoing chemotherapy. For up to ninety days, participants were randomized to receiver either atorvastatin 20&#xa0;mg or rivaroxaban 10&#xa0;mg daily. The level of plasma of IL-6, CRP, TF, F1 + 2, and D-dimer were assessed 24&#xa0;h before chemotherapy, 30, 60, and 90&#xa0;day after chemotherapy. The latest observation carried forward (LOCF) approach was used to examine the data. The laboratory results were evaluated using an independent T test or Mann-Whitney U test prior to and after chemotherapy.</p> Results <p>Eighty-six randomized patients were enrolled, although both groups showed a decreasing trend in plasma level of IL-6, CRP, TF, F1 + 2, and D-dimer, there were no significant differences between the two groups (<i>p</i> &gt; 0.05). In the atorvastatin group, there was a significant correlation between delta level of IL-6 and F1 + 2 (<i>r</i> = 0.313, <i>p</i> = 0.043) and delta level of CRP and F1 + 2 (<i>r</i> = 0.398, <i>p</i> = 0.009), whereas in the rivaroxaban group there was a significant correlation between delta CRP and D-dimer level (<i>r</i> = 0.387, <i>p</i> = 0.009).</p> Conclusion <p>Atorvastatin decreases IL-6 and CRP level, which also decreases F1 + 2 level. Atorvastatin did not substantially differ from rivaroxaban in decreasing plasma levels of inflammatory biomarkers IL-6, CRP, and coagulation activation biomarkers TF, F1 + 2, D-dimer in high-risk cancer patients undergoing chemotherapy.</p> Trial registration <p>ISRCTN71891829, Registration Date: 17/12/2020.</p>