For cells of the innate immune system to mount a host defence response to infection, they must recognize products of microbial pathogens such as lipopolysaccharide (LPS), the endotoxin secreted by Gram-negative bacteria¹. These cellular responses require intracellular signalling pathways, such as the four MAP kinase (MAPK) pathways^2–6. In mammalian cells the MAPK p38 is thought to play an important role in the regulation of cellular responses during infection through its effects on the expression of proinflammatory molecules^7–9. One means of understanding the role of p38 in these responses is to identify proteins with functions regulated by p38-catalysed phosphorylation. Here we demonstrate a link between the p38 pathway and a member of the myocyte-enhancer factor 2 (MEF2) group of transcription factors. We found that in monocytic cells, LPS increases the transactivation activity of MEF2C^10–12 through p38-catalysed phosphorylation. One consequence of MEF2C activation is increased c-jun gene transcription. Our results show that p38 may influence host defence and inflammation by maintaining the balance of c-Jun protein consumed during infection.