Multiple myeloma is the second most prevalent type of blood cancer, representing approximately 1% of all cancers and 2% of all cancer deaths. There is therefore a strong need to identify critical targets in multiple myeloma neoplasia and progression. Cancerous inhibitor of PP2A (CIP2A) is a human oncoprotein that regulates cancer cell viability and anchorage-independent growth and induces apoptosis. The present study investigated CIP2A function in the human multiple myeloma cell lines RPMI-8226 and NCI-H929 to determine whether it can serve as a potential therapeutic target. CIP2A was silenced in the cells by transfection of short interfering RNA and cell proliferation and apoptosis were evaluated by a tetrazolium salt-based assay and flow cytometry, respectively. CIP2A knockdown inhibited proliferation and induced apoptosis in RPMI-8226 and NCI-H929 cells and decreased the phosphorylation of phosphoinositide 3-kinase (PI3K) p85, AKT1, and mammalian target of rapamycin (mTOR) without affecting total protein levels. Treatment of CIP2A-depletion cells with insulin-like growth factor 1 decreased the effects of CIP2A inhibition on cell viability and apoptosis. These results indicate that CIP2A modulates myeloma cell proliferation and apoptosis via PI3K/AKT/mTOR signaling and suggest that it can potentially serve as a drug target for the treatment of multiple myeloma.