Neocytolysis, i.e. destruction of young red blood cells (RBC), occurs in astronauts over the spaceflight first days. Due to microgravity, a central blood pooling occurs. The consequent increased diuresis and decreased plasma volume cause haematocrit increase. Therefore, EPO synthesis is down regulated, a fact that associated to neocytolysis, leads to a fast reduction of RBC mass. We have analysed a panel of plasma and RBC parameters which can be related to young red cells destruction on blood samples drawn from four astronauts before and after a 10-11 spaceflight days. After the spaceflight, ferritin plasma levels were increased in three subjects, indicating a possible haemolytic process recently occurred. The percentage of young RBCs was decreased and a small number of those left over exposed phosphatydilserine (PS) on the outer membrane layer, thereby showing an “apoptotic-like” phenotype, able to trigger ingestion by macrophages. A decreased expression of both “protective” membrane molecules CD55 and CD47 on young RBCs was also observed.