The association between hyperglycemia and outcomes during chemotherapy has been reported in several tumors, including multiple myeloma (MM). However, the underlying mechanism of how hyperglycemia affects the survival of MM cells during chemotherapy remain to be elucidated. MM cells were cultured in 10 mM glucose with or without chemotherapeutic agents. Following treatment of MM cells with dexamethasone or bortezomib, an MTT assay was used to evaluate the toxicity of dexamethasone or bortezomib on cell proliferation, and changes of reactive oxygen species (ROS) level were detected by flow cytometry (FCM) analysis. Small interference RNA (siRNA) was applied to inhibit the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). Expressions of PGC-1α and antioxidant factors such as superoxide dismutase 2 (SOD‑2), glutathione peroxidase 1 (GPX-1), and catalase (CAT) were measured by RT-PCR prior to and following treatment. The results showed that the level of PGC-1α in MM cells cultured in high-glucose medium was upregulated prior to and following treatment of chemotherapeutic agents, and these cells showed less fold-change of ROS after insult of drugs, when compared to the control. Genes encoding antioxidant factors such as SOD-2 and CAT were also upregulated. Inhibition of PGC-1α enhanced the toxicity of antitumor agents, associated with reduced expression of antioxidant factors, and elevated level of ROS. The present findings suggested that hyperglycemia may influence the anticancer effect of chemotherapeutic agents in MM by upregulating the expression of PGC-1α and associated antioxidant factors. Inhibition of PGC-1α or control of hyperglycemia may be beneficial in improving the efficacy of chemotherapy in MM patients with diabetes.