Drug resistance, a major challenge in cancer chemotherapy, is a result of several mechanistic alterations including resistance to apoptosis. Apoptosis is a well-controlled cell death mechanism which is regulated by several signaling pathways. Alterations in structure, function, and expression pattern of the proteins involved in the regulation of apoptosis have been linked to drug resistance. Programmed Cell Death 10 (PDCD10) protein is recently associated with the regulation of cell survival and apoptosis. However, the role of PDCD10 in drug resistance has not been clearly established. Here, we aimed to figure out the role of PDCD10 in resistance to anti-cancer agents in different cell lines. We found that PDCD10 expression was cell- and anti-cancer agent-specific; down-regulated in doxorubicin- and docetaxel-resistant MCF7 cells while up-regulated in doxorubicin-resistant HeLa cells. Down-regulation of PDCD10 expression by siRNA in parental MCF7 cells increased the resistance while it increased sensitivity in doxorubicin-resistant HeLa cells. Similarly, over-expression of PDCD10 in parental HeLa cells increased the resistance to doxorubicin while it re-sensitized doxorubicin-resistant MCF7 cells. Moreover, the alterations in PDCD10 expression led to changes in caspase 3/7 activity and the levels of apoptosis-related genes. Our results point out a possible dual role of PDCD10 in drug resistance for the first time in the literature and emphasize PDCD10 as a novel target for reversal of drug resistance in cancer.