P38 inhibitors are potent anti-inflammatory agents with distinctive mechanism of action from corticosteroid; the potential combined use of both anti-inflammatory agents could be an effective treatment for inflammatory lung disease; however, the impact of such combination on the homeostasis of immune response was poorly understood. To investigate the combined effect of dexamethasone (DEX) and/or SB203580 on tumor necrosis factor (TNF)-α (pro-inflammatory) and interleukin (IL)-10 (anti-inflammatory) secretion in mouse alveolar macrophage cell line. Secreted TNF-α and IL-10 were measured by ELISA. Phosphorylated STAT3 were investigated using Western blotting and immunocytochemistry. Pre-treatment of DEX or SB203580 inhibited lipopolysaccharide (LPS)-stimulated IL-10, TNF-α secretion, and STAT3 phosphorylation. Combined use of both agents showed stronger inhibitory effect. Combining DEX and SB203580 showed strong inhibition on the LPS-induced IL-10 secretion and STAT3 phosphorylation, which might reflect a very important drawback from the combined use of both anti-inflammatory agents.