Objective To study the mechanism by which recombinant human hepatitis B virus core antigen (rhHBcAg) induces interleukin-15 (IL-15) secretion in myeloid dendritic cells (mDCs). Methods Human peripheral blood monocytes were isolated from peripheral blood of healthy volunteers by Dynabeads Untouched Human monocytes kit. We obtained mDCs by culturing the monocytes in the presence of GM-CSF, IL-4 and TNF-α. In one group, mDCs were cultured in RPMI1640 and stimulated by rhHBcAg at the final concentration of 10 μg/mL for 1, 2, 3, 4, 5, 6 days. In another group, mDCs were incubated with 25 μmol/L LY294002 (PI3K/Akt inhibitor), 1 μmol/L SB203580 (p38MAPK inhibitor), 100 nmol/L SP600125 (JNK inhibitor) and 150 nmol/L U0126 (ERK inhibitor) for 1 hour separately, and then stimulated by 10 μg/mL rhHBcAg for another 48 hours. Cells and supernatants were collected, and IL-15 mRNA expression level, IL-15 protein level, phosphorylation rate of MAPK and PI3K/Akt signaling pathway were detected by real-time qPCR, ELISA and Western blotting, respectively. Results IL-15 mRNA and protein levels significantly increased in rhHBcAg stimulation group compared with non-stimulated group. IL-15 protein level in p38 inhibitor pretreatment group was significantly lower than that in rhHBcAg stimulation group, but that in PI3K/Akt-, JNK- and ERK-inhibitor pretreatment groups were not obviously changed. Conclusion rhHBcAg promotes IL-15 expression in mDCs via p38 MAPK signaling pathway.