Inflammation, ischemia or the micro environment of solid tumors is often accompanied by a reduction of extracellular pH (acidosis). The effect of acidosis on the expression of various inflammatory markers and on signaling pathways involved was studied in monocytic cells and macrophages. In monocytic cell lines acidosis led to a reduction in expression of the inflammatory mediators IL-1ß, IL-6, TNF-α, MCP-1, COX-2 and osteopontin. In RAW264.7 macrophage cell line IL-1ß, COX-2 and iNOS expression was increased, whereas MCP-1 was reduced similar to the effect in monocytic cells. Neither ERK1/2 nor CREB signaling was stimulated by the reduction of extracellular pH. However, p38 was activated by acidosis in RAW264.7 cells. In conclusion, acidosis may impede the recruitment of immune cells, but fosters inflammation when macrophages are present by increasing the level of COX-2 and iNOS and by functionally forcing up the phagocytic activity.