Low density lipoproteins (LDL) inhibit the Na +/H + antiport and thereby sensitize platelet towards agonist. However, mechanisms underlying the suppressing effect of LDL on Na +/H + exchange are unclear. We here show that the lowering of intracellular pH and the suppression of the sodium propionate-induced Na +/H + exchange in the presence of LDL are abolished by SKF86002, a selective inhibitor of p38 MAP kinase (p38 MAPK). The inhibitory effect of LDL on Na +/H + exchange was mimicked by H 2O 2, which directly activates p38 MAPK. Exposure of platelets to LDL or H 2O 2 led to phosphorylation of p38 MAPK, its upstream regulator MAP kinase kinase 3/6 (MKK 3/6), and its downstream target heat shock protein 27 (HSP27), and this effect was abrogated in SKF86002-pretreated platelets. In addition, both LDL and H 2O 2 produced the SKF86002-sensitive phosphorylation of an oligopeptide encompassing p38 MAPK phosphorylation sequence derived from NHE-1, a major Na +/H + exchanger in platelets. We further show that the sensitizing effects of LDL on the thrombin-induced platelet activation, as reflected by aggregation and granule secretion, are abolished in cells pretreated with SKF86002. We conclude that activation of p38 MAPK is required for the inhibitory effect of LDL on Na +/H + antiport and thereby for LDL-dependent sensitization in human platelets.