Cytokines are critical to pathogenesis of inflammatory disorders. So inhibition of their action provides therapeutic benefits in various diseases. Although inhibition of inflammation caused by intraperitoneally administered LPS can identify cytokine modulators, this inflammatory test-agent does not allow one to determine overall anti-inflammatory potential. Functional characteristics of Carrageenan (Cara)-induced edema were valuable for identification of nonsteroidal anti-inflammatory drugs (NSAIDS). Hence, the potential of LPS-induced paw inflammation was investigated and compared to that by Cara. Stimulation of isolated rat peritoneal exudates cells (PEC) with 10 ng/ml LPS, but not Cara, induced IL-6 (3.04±0.2 ng/ml) and TNFα; (1.030.09 ng/ml). At least 100 mg/ml Cara was necessary for detection of IL-6 (2.03±0.1 ng/ml) and TNFα; (0.6+0.09 ng/ml) in PEC. Similar to Cara, subplantar administration of LPS-induced inflammatory paw edema in rats. LPS, but not Cara, induced TNFα; (2.14±0.6 ng/ml) and IL-6 (2.9±0.5 ng/ml) in serum at 1 and 3 h, respectively, which returned to basal levels by 5 h. LPS-induced serum TNFα; (sTNFα;) levels closely paralleled paw swelling and its neutralization by anti-TNFα; antibody or inhibition by pentoxifylline and nimesulide correlated with inhibition of inflammation. Similar to earlier reports, rofecoxib induced sTNFα; at 30 mg/kg and exhibited pro-inflammatory effect by enhancing paw swelling. LPS-induced edema provides a useful functional model for identification of cytokine modulating anti-inflammatory agents.