Jehovah's Witnesses (JW) refuse allogeneic blood transfusions and therefore pose a unique challenge in case of major surgery. This retrospective study reviewed an experience with JW patients who were undergoing open heart surgery. By using patient blood management strategies, 35 adult JW patients underwent cardiac surgery at Kepler University Hospital in Linz, Austria between 2008 and 2017. Outcomes were compared with patients who accepted blood transfusions (non-JW patients) by using propensity score matching. There were no significant differences in clinical and operative data between the groups. Twelve JW patients (34.3%) were pretreated with erythropoietin and iron, with a preoperative increase in mean hemoglobin of 2.0 g/dL. On admission, hemoglobin was 14.1 ± 1.1 g/dL in JW patients, compared with 13.2 ± 2.0 g/dL in non-JW patients (P = .022). The hematocrit in JW patients was higher throughout the hospital stay, even though 51.4% of non-JW patients received allogeneic red blood cell transfusions. The perioperative red blood cell loss was significantly lower in JW patients than in non-JW patients (619 ± 420 mL vs 929 ± 520 mL; P = .010). Major complication rates were not different between the groups. The hemoglobin at discharge was 11.5 ± 1.5 g/dL in JW patients compared with 10.3 ± 1.3 g/dL in non-JW patients (P < .001). In-hospital mortality was 2.9% in each group, and long-term survival was comparable. By implementing patient blood management, open heart surgery in JW patients can be performed with low morbidity and mortality. Preoperative optimization of hemoglobin and minimization of perioperative blood loss are cornerstones in the prevention of blood loss, anemia, and transfusions.