Spaceflight conditions have a significant impact on a number of physiological functions due to psychological stress, radiation and reduced gravity. To explore the effect of the flight environment on immunity, C57BL/6NTac mice were flown on a 13-day space shuttle mission (STS-118). In response to flight, animals had a reduction in liver, spleen and thymus masses compared to ground (GRD) controls (p<0.005). Splenic lymphocytes, monocyte/macrophages and granulocyte counts were significantly reduced in the flight (FLT) mice (p<0.05). Although spontaneous blastogenesis of splenocytes in FLT mice was increased, response to lipopolysaccharide (LPS), a B cell mitogen derived from E. coli, was decreased compared to GRD mice (p<0.05). Secretion of IL-6 and IL-10, but not that of TNF- by LPS-stimulated splenocytes was increased in FLT mice (p<0.05). Finally, many of the genes responsible for scavenging ROS were up-regulated after flight. These data indicate that exposure to the spaceflight environment can increase anti-inflammatory mechanisms and change the ex vivo response to lipopolysaccharide (LPS), a bacterial product associated with septic shock and a prominent Th1 response.