Background: Complications related to extracorporeal circulation remain serious. Although a minimal invasive extra corporeal circulation (MiECC) system was developed to cope with these complications, its effectivity on patient-related outcomes such as blood loss remain uncertain. Therefore, the aim of this study is to compare MiECC to an advanced standard system with respect to blood loss. Methods: A total of 128 adult patients undergoing elective isolated aortic valve replacement were enrolled in a randomized clinical trial. Patients who had undergone previous heart surgery and with preexisting kidney failure were excluded. The primary end point was postoperative blood loss after 12 hours and at drain removal. Secondary end points included intensive care and total length of stay and intubation time. At 1 hour and 12 hours after surgery, clinical laboratory data were determined. Early clinical outcomes and long-term survival were determined. Results: MiECC patients (n = 63) had a significant lower blood loss (230 mL, 95% confidence interval: 203 to 261 mL) than regular patients (n = 62) after 12 hours (288 mL, 95% confidence interval: 241 to 344 mL, p = 0.04). A preservation of hemoglobin levels 1 hour and 12 hours after surgery in the MiECC group were observed (p < 0.001). No difference was found in early clinical outcomes and long-term survival. Conclusions: This randomized controlled trial compares MiECC and an advanced system for aortic valve replacement with blood loss as primary end point. We conclude that using MiECC is clinically equal for short- and long-term follow-up regarding blood loss. Clinical trial registration: NTR3378.