Despite the demonstrated success of multiple anticoagulation therapies for post-operative prophylaxis of thromboembolic disease in lower extremity arthroplasties, each modality comes with a unique set of limitations. Thus, the ideal anticoagulation medication which provides adequate therapy with minimal cost, complications, or added patient work is yet to be defined. One promising novel thrombophylactic supplement is fish oil, as many preliminary clinical trials have demonstrated a protective effect of fish oil against thrombosis in multiple clinical settings. In addition, others have demonstrated synergistic effect when combined with aspirin. However, there are paucity of studies that compared combined aspirin and fish oil therapy for venous thromboembolism prophylaxis with other pharmacological agents, especially in the field of orthopaedics. Therefore, this study evaluated: (I) risk of post-operative deep vein thrombosis (DVT) and pulmonary embolism (PE), and (II) bleeding complications; among patients who had primary total knee arthroplasty (TKA) and received one of the following regimens: (i) 325 mg aspirin and mechanical pulsatile stocking; (ii) rivaroxaban; or (iii) 325 mg aspirin and 1,000 mg fish oil. This was a 6-year prospective study analyzing the postoperative thromboembolic prophylaxis received by patients who underwent primary TKA. Patients who had a previous history of thromboembolic disease were excluded from the study due to an increased risk of recurrent clot formation. A total of 850 patients were enrolled. A total of 300 patients enrolled between October 2011 and June 2013 received 325 mg aspirin and mechanical pulsatile stocking, while 250 patients enrolled between June 2013 and December 2014 received rivaroxaban. A total of 300 patients enrolled between January 2015 and July 2017 received 325 mg aspirin and 1,000 mg fish oil. Major venous thromboembolic events (VTEs) and bleeding complications within the first 90 days post-operatively were recorded in each cohort. The odds ratios (ORs) and 95% confidence intervals (CIs), for thromboembolic and bleeding events were calculated and compared between the aspirin and fish oil cohort vs. aspirin and pulsatile stocking cohort, and aspirin and fish oil cohort vs. rivaroxaban cohort. A P value of <0.05 was used to determine statistical significance. A total of 25 DVT events were recorded including 1 of 300 (0.33%) in the aspirin and fish oil cohort, 22 of 300 (7.33%) in the aspirin and pulsatile stocking cohort and 2 of 250 (0.8%) in the rivaroxaban cohort. When comparing ORs, patients who received aspirin and fish oil demonstrated significantly lower risk for thromboembolic events when compared to the aspirin and pulsatile stocking group (OR: 0.045; 95% CI: 0.0061-0.3394; P<0.05). When compared to the rivaroxaban cohort the ORs did not differ significantly (OR: 0.416; 95% CI: 0.0376-4.6223; P>0.05). In addition, no PE events were recorded in any of the cohorts. When compared to rivaroxaban, the fish oil and aspirin cohort demonstrated significantly lower incidence of bleeding episodes (1 of 300, 0.33% vs. 30 of 250 patients, 12%; OR: 0.0278; 95% CI: 0.0038-0.2051; P<0.05). No bleeding events were recorded in the aspirin and pulsatile stocking cohort. This study demonstrated the potentially synergistic anti-thromboembolic effect of aspirin and fish oil in the prevention of post-operative venous thromboembolism in primary TKA patients. Based on the results from this study, the authors conclude that the combination of aspirin and fish oil maybe an excellent thromboprophylactic modality for patients to use after TKA. These results warrant further, larger prospective studies analyzing the use of fish oil supplements in VTE prophylaxis.