Protein-bound polysaccharide-K (PSK) is extracted from Coriolus versicolor (CM101) and is clinically used in combination therapy for gastrointestinal cancer and small-cell lung carcinoma. We have previously demonstrated that PSK induces apoptosis and inhibites proliferation of promyelomonocytic leukemia HL-60 cells, but the signaling pathway for this action remains to be elucidated. In HL-60 cells, the mitogen-activated protein kinase (MAPK) pathway has been reported to be involved in stimuli-induced apoptosis. Therefore, involvement of the p38 MAPK pathway in PSK-induced apoptosis was herein investigated.HL-60 cells were used in this study. Western blotting was performed to detect phosphorylated p38 MAPK. A p38 MAPK inhibitor, SB203580, was used to examine the roles of p38 MAPK in PSK-induced apoptosis and growth inhibition.PSK induced p38 MAPK phosphorylation. Co-treatment with SB203580 blocked PSK-induced apoptosis, caspase-3 activation and growth inhibition.The p38 MAPK pathway plays an important role in PSK-induced apoptosis.