The efficacy of an integrated autotransfusion regimen, including pre-donation and perioperative salvage of autologous blood, was prospectively evaluated in 2884 patients undergoing total hip (n=2016) or knee arthroplasty (n = 480), and hip revision (n = 388) with either balanced general, regional, or integrated epidural/general anaesthesia. Allogenic concentrated red blood cells were transfused in the presence of symptomatic anaemia or when haemoglobin concentration was < 6gdL−1 (10gdL−1 in patients affected by cerebrovascular or coronary artery disease) after all salvaged and pre-donated autologous blood had been transfused. A total of 278 patients (9.6%) received allogenic blood. Risk factors for allogenic blood transfusion were: preoperative haemoglobin concentration < 10gdL−1 (after autologous blood pre-donations) (Odds ratio: 8.7; 95% CI: 6.5–16.8; P=0.004), hip revision versus hip or knee arthroplasty (Odds ratio: 5.8; 95% CI: 3.9–8.5; P=0.0001) and inability in obtaining the number of predonations required by the Maximum Surgery Blood Order on Schedule (Odds ratio: 3.4; 95% CI: 2.7–4.1; P=0.0001). The incidence of perioperative complications, including wound infection and haematoma, as well as myocardial ischaemia, respiratory failure and thromboembolic complications, was higher in those patients requiring allogenic blood transfusion (29.8%) than that observed in patients receiving only autologous blood (6.6%) (P=0.0005); while the mean time duration from surgical procedure to patient discharge from the orthopaedic ward was shorter in those patients not receiving allogenic blood transfusion (12 days; 25–75th percentiles: 8–14 days) than in those patients who required perioperative transfusion with allogenic blood (15 days; 25–75th percentiles: 10–17 days) (P=0.0005). In conclusion, this prospective study highlighted the clinical relevance of applying an extensive and integrated autotransfusion regimen in order to reduce allogenic blood transfusion and associated complications in patients undergoing major joint replacement.