OBJECTIVES: Classical Hodgkin lymphoma (cHL) is identified by the appearance of Hodgkin and Reed-Sternberg cells. A20 and CYLD are deubiquitinating enzymes involved in negatively regulating NF-κB-mediated immune response. Vincristine (Vinc) and doxorubicin (Dox) are classical antitumor drugs, in which Dox serves a key role in chemotherapy against cHL and Vinc induces disruption of microtubule function that inhibits mitosis of cancer cells. Little is known about the roles of A20/CYLD in regulating macrophage function from cHL patients upon treatment with Vinc or Dox. This study, therefore, asked whether A20/CYLD expression affects function of macrophages in cHL cases. MATERIALS AND METHODS: Macrophages from cHL patients differentiated from bone marrow cells were exposed to Vinc or Dox. Gene expression levels were determined by real time-qPCR, cell maturation, apoptosis and phagocytosis by flow cytometry, and cytokine release by ELISA. RESULTS: Dox induced maturation, apoptosis, and phagocytosis of macrophages in cHL cases. Moreover, the percentage of CD68(+)CD40(+), but not CD68(+)CD86(+) cells as well as levels of IL-1β were further enhanced when exposed to A20 siRNA, whereas the absence of CYLD unaltered macrophage function in cHL patients. Importantly, the increased numbers of A20-sensitive CD68(+)CD40(+) and Annexin V(-)PI(+) cells as well as enhanced levels of caspase 3 were abolished in the presence of mTOR inhibitor Everolimus. CONCLUSION: The present study indicates that Dox-induced macrophage maturation and apoptosis are dependent on A20 expression through mTOR signaling. Moreover, inhibition of Dox-induced macrophage maturation in the patients with low A20 expression by Everolimus might represent a promising therapy for A20-sensitive cHL cases.