Impairment of the ability to mount an inflammatory response is associated with death from adult critical illness. This phenomenon, characterized by reduced monocyte production of proinflammatory mediators such as tumor necrosis factor alpha (TNF-alpha), is poorly understood in children. We hypothesized that differential expression of inflammation-related genes would be seen in monocytes from children with adverse outcomes from multiple organ dysfunction syndrome (MODS). Ex vivo lipopolysaccharide (LPS)-induced TNF-alpha production and plasma cytokines were prospectively measured biweekly in children with dysfunction of two or more organs. Concomitantly, monocyte expression of 28 pro- and anti-inflammatory genes [cytokines, Toll-like receptor (TLR)/nuclear factor kappaB (NF-kappaB) signaling pathway members, inflammasome elements] was measured. Thirty children (22 survivors, eight nonsurvivors) were evaluated. High mRNA levels for interleukin (IL)-10, IL-1 receptor-associated kinase (IRAK-M), and the putative inflammasome inhibitor pyrin were associated with death (p < or = 0.02). Plasma IL-10 levels were higher and ex vivo TNF-alpha production was lower in nonsurvivors (p < 0.05). Among survivors, high mRNA levels for IL-10, IRAK-M, pyrin, IRAK1, or TLR4 were associated with longer durations of pediatric intensive care unit (PICU) stay and mechanical ventilation (p < or = 0.02). These data suggest that adverse outcomes from pediatric MODS are associated with an anti-inflammatory monocyte mRNA phenotype. Future studies are warranted to explore mechanisms of immunodepression in pediatric critical illness.