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Malaria causes 300-500 million clinical cases and 1-3 million deaths per year, the majority of which occur in young African children. Ingestion of hemozoin by peripheral blood mononuclear cells (PBMC) initiates the cytokine-mediated cascade of immune dysregulation in malaria. Innate immunity plays a critical role in protective responses against infection, which are determined by an appropriate balance between pro- and anti-inflammatory mediators. Pro-inflammatory mediators (TNF-α, IL-12, IFN-γ) that control parasitemia also contribute to pathology. Over-production of immunomodulatory cytokines (TGF-β, IL-10) suppresses the protective pro-inflammatory immune response. The effects of hemozoin on hematological outcomes and inflammatory mediator production in children with malarial anemia and the temporal kinetics of hemozoin-induced cytokine dysregulation in cultured PBMC were investigated in this study. Hematological analyses of healthy control (HC), uncomplicated malaria (UM), mild malarial anemia (MlMA), moderate malarial anemia (MdMA), and severe malarial anemia (SMA) groups revealed that age, temperature, and all erythrocyte, leukocyte, and platelet indices were significantly different between clinical categories. Neither parasitemia nor the prevalence of high density parasitemia (HDP) differed significantly between clinical groups. Stratification of study participants according to proportion of pigment-containing monocytes (PCM) demonstrated that parasitemia, HDP, temperature, and most leukocyte, erythrocyte, and platelet indices were significantly different between 0%, ≤ 10%, and > 10% PCM categories. The > 10% PCM category contained children with the lowest hemoglobin, hematocrit, and erythrocyte counts and the greatest proportion of children with SMA. Plasma IFN-α, IL-4, IL-6, IL-10, and IL-12p40/p70 levels differed significantly between clinical categories but not between UM and SMA groups. Plasma IFN-α, IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-10, and IL-12p40/p70 were not significantly associated with % PCM. β-hematin-induced IL-1β, IL-2, IL-6, IL-12p35, IL-12p40, IL-18, IFN-α, IFN-γ, TNF-α, LT-α, NOS-2A, COX-1, COX-2, IL-4, IL-10, and TGF-β expression in cultured PBMC revealed a pro-inflammatory response that varied in magnitude among individuals. Importantly, innate inflammatory mediators modulate the adaptive immune response to Plasmodium parasites. Of public health significance, a better understanding of the molecular mechanisms governing these responses will facilitate the development of more immunogenic vaccines, through inclusion of cytokines or other compounds that activate the innate immune system.