Epstein-Barr virus (EBV) infection is closely related to carcinogenesis of various cancers, and is also associated with the development of drug resistance in cancer stem cells. However, in EBV-positive cancer cells, the mechanistic details of the downstream signaling and the connection of PI3K with the NF-kappa B pathway for development of drug resistance remain controversial. Diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM) cells infected by EBV display drug resistance-related proteins (MDR1, MRP1 and MRP2) and stem cell markers (OCT4 and SOX2). EBV-infected HT (HT/EBV) and H929 (H929/EBV) cells activated p110 delta expression, but downregulated the expression of p110 alpha and p110 beta. A combination of CAL-101, a p110 delta-specific inhibitor, with bortezomib treatment of HT/EBV cells synergistically suppressed proliferation, reduced levels of drug resistance-related proteins, activated caspase cleavage and recovered expression of p110 alpha/p110 beta. Additionally, co-treatment with CAL-101 and bortezomib attenuated the expression of OCT4 and SOX2 via inhibition of activated NF-kappa B. Co-treatment with CAL-101 and bortezomib also attenuated drug resistance and NF-kappa B activity of EBV-infected H929 cells. Our results provide supportive evidence for the clinical application of CAL-101 and bortezomib to treat EBV-infected hematologic cancer.