Solid tumors exhibit a specific microenvironment (e.g. acidosis), which effects tumorporgression, but also cancer-associated fibroblasts (CAFs). Thus, the effect of metabolic acidosis (pH 6.6) on the expression of inflammatory mediators (TNFα, COX-2, iNOS, MCP-1, OPN) considering the involvement of MAP-kinases ERK1/2 and p38 and underlying signaling pathways was investigated in fibroblasts (NRKF cells). By using real time-PCR the alteration in gene expression was analyzed. Phosphorylation of ERK1/2, p38 and CREB was detected by western blot. Additionally, the dependence of gene expression on ERK1/2 and p38 signaling was examined. Phosphorylation of ERK1/2, p38 and CREB was increased (short-term) at pH 6.6. Gene expression of TNFα, COX-2, iNOS was increased mediated depending on p38. Long-term acidosis led to anti-inflammatory effects (gene expression of TNF α, COX-2, MCP-1, OPN decreased). In this study we showed, that metabolic acidosis influences inflammatory programs in fibroblasts, which creates a parainflammatory environment that may impact on tumor cell behavior as well.