The proto-oncogene SET/I2PP2A, an inhibitor of the phosphatase PP2A and a potential therapeutic target for cancer, interacts with the RhoGTPase Rac1 and regulates cell motility. SET is primarily nuclear but can readily translocate to the cytoplasm. Here, we investigated this translocation in more detail. Using an image analysis method to analyse nucleo-cytoplasmic shuttling of YFP-SET, we find that the protein shows repetitive shuttling in a seemingly random fashion. We found that Rac1 activity increases the frequency of these nuclear exit events of SET. In search for cellular activators of this event, we found FTY720 (fingolimod), an immunomodulator and activator of PP2A, to rapidly induce nucleo-cytoplasmic translocation of SET. Subsequently, SET accumulates in cytoplasmic aggregates of unknown nature. Moreover, we observed that the nuclear pool of Rac1 translocates simultaneously with SET, both during spontaneous as well as FTY720-induced translocation. Finally, FTY720-induced nuclear exit is dependent on the nuclear exporter CRM1, on PP2A activity as well as on microtubule dynamics. These results show that the immunomodulator and PP2A activator FTY720, induces rapid nucleo-cytoplasmic shuttling of SET, suggesting that SET translocation is part of a negative feedback loop. This data may be relevant to the potential use of FTY720 in the treatment of leukemias and inflammatory disorders.