Background: Total hip arthroplasty (THA) has been highlighted as the best treatment option for ankylosing spondylitis (AS) patients with advanced hip involvement. The huge blood loss associated with THA is a common concern of postoperative complications. Disease activity is a specific reflection of systematic inflammation of AS. The purpose of this study was to determine the effect of disease activity on blood loss during THA in patients with AS. Methods: Forty-nine patients with AS who underwent unilateral THAs were retrospectively studied. Ankylosing Spondylitis Disease Activity Score (ASDAS) was employed to evaluate the disease activity. Orthopedic Surgery Transfusion Hemoglobin European Overview (OSTHEO) formula was used to assess the surgical blood loss. The patients were divided into active group (ASDAS≥1.3; n = 32) and stable groups (ASDAS< 1.3; n = 17) based on the ASDAS. Peri-operative laboratory values, plain radiographs, intra-operative data, transfusion volume, and use of hemostatic agents were recorded and statistically analyzed. Results: The ASDAS, pre-operative C-reactive protein level, erythrocyte sedimentation rate, and fibrinogen concentration in the active group were higher than the stable group (all P < 0.05); however, the pre-operative hemoglobin concentration and albumin level were higher in the stable group (both P < 0.05). The total blood loss during THA in stable patients was 1415.31 mL and 2035.04 mL in active patients (P = 0.006). The difference between the two groups was shown to be consistent after excluding the gender difference (P = 0.030). A high transfusion rate existed in both groups (stable group, 76.47% with an average of 1.53 units; active group, 84.37% with an average of 2.31 units), but there was no significant difference between the two groups (both P > 0.05). Compensated blood loss, corresponding to transfusion, was noted significantly more in the active group compared to the stable group (P = 0.027). There was no significant difference with regard to functional recovery (P > 0.05). Conclusion: Active AS patients are at high risk for increased blood loss during THA compared to stable patients. The underlying mechanism includes disorders of the coagulation and fibrinolytic systems, poor nutrition status, osteoporosis, imbalance of oxidative-antioxidative status and local inflammatory reaction. It is strongly recommended to perform THA in AS patients with stable disease.