The goal of the present study was to evaluate the activation patterns of p38 mitogen-activated protein kinase (MAPK) in myeloproliferative disorders (MPDs) and myelodysplastic syndromes (MDSs). Phosphorylated (activated) p38 MAPK was analyzed immunohistochemically in formalin-fixed decalcified bone marrow core biopsy specimens from 32 MPD, 33 MDS, and 11 control cases. Moderate p38 activation was commonly seen in MDS, whereas weak p38 activation was seen in all MPD cases and all control cases but 1 in the erythroid lineage. In myeloid and megakaryocytic lineages, strong p38 activation was more commonly observed in MDS compared with MPD (myeloid, 22/33 vs 2/32; P < .0001; megakaryocytic, 18/23 vs 5/32; P < .0001) and control (myeloid, 22/33 vs 2/11; P = .012; megakaryocytic, 18/23 vs 3/9; P = .035) cases. Furthermore, weak p38 activation was observed in myeloid and megakaryocytic lineages in MPD compared with control (myeloid, 15/32 vs 1/11; P = .033; megakaryocytic, 16/32 vs 0/9; P = .007) cases. Increased p38 MAPK activation may have a role in inhibiting hematopoiesis leading to cytopenias in MDS, and relatively decreased p38 activation in MPD might promote hematopoiesis, resulting in cytosis.