The plasma levels of inter-α inhibitor proteins (IAIPs) are decreased in patients with sepsis and the reduced levels correlate with increased mortality. In the present study, we examined the beneficial effects of IAIPs on human neutrophils in the treatment of sepsis. We demonstrated that IAIPs induced a spherical shape of neutrophils that was smaller in size with a smooth cellular surface in a concentration-dependent manner. IAIPs inhibited the spontaneous release of reactive oxygen species (ROS) in a concentration-dependent fashion. ROS inhibition was associated with reduction in p47phox phosphorylation on Ser328. IAIPs inhibited the NETosis that is alive consistent with the concentration-dependent inhibitory effects of IAIPs on ROS production. The inhibitory regulation of CD162 (PSGL-1) expression by IAIPs demonstrated that the suppressive effects of IAIPs on the interaction between neutrophils and other effector cells attenuates the inflammatory response. IAIPs also inhibited Zn2+-induced PS expression and aggregation of erythrocytes. Our results suggest that IAIP-induced morphological changes that render neutrophils quiescent, reduce production of ROS, inhibit immunothrombosis during polymicrobial infections and erythrocytes aggregation. Thus, IAIP plays a key role in controlling neutrophil activation and eryptosis.