Sepsis is a syndrome associated with excessive inflammation. Since mortality from sepsis remains high, more laboratory research is needed to provide insight into more effective ways to use novel, potentially more beneficial agents in sepsis. We investigated the ex vivo immunomodulatory effect of a novel polyclonal Ab preparation, trimodulin, containing IgM (∼23%), IgA (∼21%) and IgG (∼56%). Using whole blood and purified PBMCs from healthy volunteers and patients with sepsis, various ex vivo investigations upon endotoxin challenge and pre- and post-trimodulin treatment were performed. Endotoxin-induced TNF-α secretion was noticeably lower with than without trimodulin, implying attenuation of the hyper-responsive state. Trimodulin also lowered TLR2, TLR4, CD11b and CD64 detection on LPS/lipoteichoic acid-stimulated monocytes. These responses were observed in cells from healthy volunteers only shortly after ex vivo endotoxin stimulation and in whole blood from patients with early-stage sepsis. Furthermore, trimodulin markedly reduced lymphocyte proliferation and release of pro- and anti-inflammatory cytokines, but did not affect phagocytosis or oxidative-burst activities of endoxin-stimulated cells. Thus, trimodulin mitigated monocyte and lymphocyte hyperinflammatory responses early after endotoxin exposure. Determining whether early in vivo administration of trimodulin will elicit similar positive immunomodulatory effects and offer a clinical benefit warrants investigation.