Lipopolysaccharide (LPS), a key inflammatory component of gram-negative bacteria, induces a distinctive pattern of cytokine release that regulates inflammation. An alteration in the LPS response may play a fundamental role in the pathogenesis of a number of inflammatory diseases. Therefore, this study was conducted to determine whether chronic exposure to a low level of acephate (Ace), a commonly used organophosphate insecticide, impaired the LPS response in rats. This study showed that LPS injection in control rats caused (1) a time-dependent increase in blood lymphocyte enumeration and differentiation, and (2) a sequential increase the pro-inflammatory (interleukin-1beta (IL1beta), tumor necrosis factor-alpha (TNFalpha), interferon-gamma (INTgamma), and inducible nitric oxide synthase (iNOS)) and anti-inflammatory (interleukin-4 (IL-4), corticotropin-releasing factor (CRF), and blood corticosterone (Cort)) cytokines. The pro-inflammatory cytokines increased after 30 min, while the anti-inflammatory cytokines increased 3 h after LPS injection. An increase in proinflammatory cytokines increased lymphocyte enumeration and differentiation, while the increase in anti-inflammatory cytokines re-established homeostasis. In comparison to the control rats, the Ace-exposed rats exhibited (1) lower levels of IL1beta, TNFalpha and iNOS, (2) higher levels of CRF and Cort, and (3) lower levels of IL-4 in blood and/or brain samples. The abnormal cytokine production may be associated with abnormal phenotypic distribution of B and T cells. Blood IgMhi IgDhi, IgMlo IgDlo and CD8+ CD45RA- CCR7+ cells were elevated, while IgMlo IgDhi, IgMhi IgDlo, IgMin IgDlo, CD8+ CD45RA+ CCR7+ and CD8+ CD45RA- CCR7 cells were depressed in Ace-exposed rats. Thus, chronic low-level Ace exposure may impair the lineage commitment in lymphocytes, possibly by altering cytokine signaling in the brain.