Objective To compare the efficacy and safety of intra-articular combined with intravenous administration of tranexamic acid (TXA) with different dosage for reducing blood loss in primary total knee arthroplasty (TKA). Methods Between January 2017 and June 2017, 90 patients suffering from unilateral osteoarthritis who underwent primary TKA were randomly scheduled to three interventions, named groups A, B, and C. Single dosage of TXA via intravenous injection (IV) and different dosages of TXA via intra-articular injection (IA) were utilized in three groups, respectively. All patients in three groups received 1 g TXA IV at 10 minutes preoperatively, and received 1, 2, and 3 g TXA IA diluted in 50 mL saline after wound closure in groups A, B and C, respectively. The age, gender, body mass index, affected side of the knee, grade of osteoarthritis, grade of America Society of Anesthesiologist, preoperative hemoglobin (Hb) concentration, platelet count, preoperative prothrombin time, and activated partial thromboplastin time were not significantly different between groups (P>0.05). The postoperative wound blood drainage, Hb concentration at 1, 3, and 7 days after operation, transfusion rate, and thromboembolic complications were observed. All patients were routinely observed for deep vein thrombosis (DVT) by the color Doppler ultrasonography at 1 week, 1 month, and 3 months after operation, and the symptomatic pulmonary embolism (PE) were observed. Results All patients in three groups were followed up 7-12 months (mean, 8.4 months). There was no significant difference in operation time between groups (P>0.05). The postoperative wound blood drainage was significantly less in groups B and C than that in group A (P<0.05), whereas no significant difference was found between group B and group C (P>0.05). Incision skin necrosis occurred in 1 case of group B and fat liquefaction occurred in 1 case of group C. The other incisions of 3 groups healed by first intention. There was no significant difference in incision complication incidence between groups. The Hb concentration was significantly higher in groups B and C than that in group A at 1, 3, and 7 days after operation (P<0.05). While between group B and group C, the significant difference of Hb concentration only existed at 1 day after operation (P<0.05). The number of patients who got blood transfusion was significantly less in group B (4 cases, 13.3%) and group C (5 cases, 16.7%) than that in group A (9 cases, 30%) (P< 0.05), but no significant difference was found between group B and group C (P>0.05). The result of color Doppler ultrasonography showed that 1 case got DVT in the contralateral calf at 3 weeks in group B. And there was no symptomatic PE in 3 groups. Conclusion Combined administration of IV and IA TXA in a clinically relevant reduction in blood loss was effective and safe in primary TKA, and no thromboembolic complication was observed. The combination of 1 g IV with 2 g IA could be the optional choice.