BACKGROUND: Transfusion of long-stored red blood cells (RBCs) is associated with decreased in vivo RBC recovery, delivery of RBC breakdown products, and increased morbidity and mortality. Reducing the burden of this RBC "storage lesion" is a major challenge in transfusion medicine. Additive solution-7 (AS-7) is a new RBC storage solution designed to improve RBC metabolism by providing phosphate and increasing buff-ering capacity. STUDY DESIGN AND METHODS: Storage quality in AS-7 was measured in a prospective, randomized, three-center trial using units of whole blood from healthy human subjects whose RBCs were stored for up to 56 days in AS-7 (n = 120) or for 42 days in the control solution AS-1 (n = 60). RESULTS: Hemolysis and shedding of protein-containing microvesicles were significantly reduced in RBCs stored in AS-7 for 42 and 56 days compared with RBCs stored in AS-1. Autologous in vivo recoveries of RBCs stored in AS-7 was 88 ± 5% at 42 days (n = 27) and 82 ± 3% at 56 days (n = 27), exceeding recoveries of RBCs stored in currently used solutions. CONCLUSION: Increasing the phosphate, pH range, and buffer capacity of a RBC storage system allowed RBCs to be stored better and longer than currently approved storage systems. AS-7 ameliorates the long-term storage lesion resulting in significantly increased viability in vitro and in vivo. R ed blood cells (RBCs) are the most commonly transfused blood products. 1 However, the occurrence of antigenic blood groups on RBCs means that large numbers of RBC units are required in the inventories of regional blood systems and hospitals to assure that needed types are readily available. 2,3 RBCs for transfusion are prepared either from whole blood collected into CPD or CP2D or from apheresis collection into CP2D or ACD-A. After being processed into components, additional nutrients are provided to the RBCs for long-term storage in the form of an additive solution (AS). 4 RBCs for transfusion may also be leukoreduced before storage. These ASs were developed to provide volume for the dilution of metabolic waste; nutrients, especially adenine; and membrane protectant sugars. The current AS allow RBCs to be stored for up to 42 days with a mean in vivo recovery at the end of storage of 82 ± 7% From the (n = 641), 12% of samples showing less than 75% recovery, and hemolysis of 0.4% (n = 14,087) or 0.5% (n = 344, unpublished). 6 These performance characteristics suggest that ASs are effective and safe, and three ASs are licensed and in use in the United States, AS-1, AS-3, and AS-5, which perform equivalently. 7-9 Additional ASs have been approved for use in other countries including SAG-M, MAP, and PAGGSM for storage for 35 to 42 days. 10-12 The use of 42-day AS-stored RBC products has allowed the development of highly efficient national blood programs with approximately 95% of donated RBCs finding a recipient in Western countries. Recent studies have raised concerns about the safety of stored RBCs associated with the development of a clinically relevant RBC storage lesion, whic...