We have previously demonstrated that constant 20 mmHg extracellular pressure increases serum-opsonized latex bead phagocytosis by PMA-differentiated THP-1 macrophages in part by inhibiting FAK and ERK. Since p38MAPK is activated by physical forces in other cells, we hypothesized that modulation of p38MAPK might also contribute to the stimulation of macrophage phagocytosis by pressure. We studied phagocytosis in PMA-differentiated THP-1 macrophages, primary human monocytes, and human monocyte-derived-macrophages (MDM). p38MAPK activation was inhibited using SB203580 or by p38MAPK-SiRNA. Pressure increased phagocytosis in primary monocytes and MDM as in THP-1 cells. Increased extracellular pressure for 30 minutes increased phosphorylated p38MAPK by 46.4±20.5% in DMSO-treated THP-1 macrophages and by 20.9±9% in primary monocytes (p<0.05 each). SB203580 (20 µM) reduced basal p38 MAPK phosphorylation by 34.7±2.1% in THP-1 macrophages and prevented pressure activation of p38. p38MAPK-SiRNA reduced total p38MAPK protein by 50-60%. Neither SB203580, in THP-1 cells and peripheral monocytes, nor p38MAPK-SiRNA, in THP-1 cells, affected basal phagocytosis, but each abolished pressure-stimulated phagocytosis. SB203580 did not affect basal or pressure-reduced FAK activation in THP-1 macrophages, but significantly attenuated the reduction in ERK phosphorylation associated with pressure. p38MAPK-SiRNA reduced total-FAK protein by 40-50%, and total-ERK by 10-15%, but increased phosphorylated ERK 1.4±0.1 fold. P38MAPK SiRNA transfection did not affect the inhibition of FAK-Y397 phosphorylation by pressure but prevented inhibition of ERK phosphorylation. Changes in extracellular pressure during infection or inflammation regulate macrophage phagocytosis by a FAK-dependent inverse effect on p38MAPK which might subsequently downregulate ERK.