Hepatic Kupffer cells (KC), the major tissue macrophage population, produce the septic response mediators, tumor necrosis factor α (TNF-α) and prostaglandin E2 (PGE2 ), and have been shown to internalize gadolinium chloride (GD), a rare earth metal of the lanthanide series. Because GD pretreatment of rats has been shown to inhibit the mortality of sepsis, we studied the secretory response to lipopolysaccharide (LPS) by KC isolated from rats injected with either saline or GD (7 mg/kg, intravenously) on the 2 days before KC isolation. Using culture conditions modified to reflect the intrasinusoidal milieu of arginine (RPMI-1640 media with 10 or 100 μmol/L arginine), KC from GD-treated rats responded to LPS (0.0025 μg/mL) with significantly (P < .01) reduced PGE2 release. In contrast, TNF-α release by treated KC was significantly (P < .05) enhanced, consistent with the loss of PGE2 autocoid inhibition of TNF-α. Calcium flux is an early signaling event in eicosanoid synthesis, and GD is known to block calcium channels. Therefore, KC were loaded with fura-2-AM to study the effect of GD on KC calcium flux. GD prevented ionomycin and platelet-activating factor (PAF)-mediated [Ca++]i increase and calcium-dependent PGE2 synthesis, while GD did not affect PGE2 synthesis when protein kinase C (PKC) was directly activated with tetradecanoylphorbolacetate (TPA). The inhibition of calcium flux and calcium-dependent PGE2 synthesis in the major cell of the monocytic phagocytic system by GD may explain the previously reported ability of this lanthanide to prevent the mortality of endotoxemia.