Immunomodulatory drugs (IMiDs) are key agents for the treatment of multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the recruitment of neo-substrates to cereblon, a substrate receptor of the E3 ubiquitin ligase complex; therefore, identification of cell specific neo-substrates is important to understand the effects of IMiDs. In clinical practice, IMiDs induce thrombocytopenia that frequently results in the discontinuation of IMiDs treatment. In the current study, we sought to identify the molecular mechanism underlying thrombocytopenia induced by IMiDs treatment. We found that IMiDs strongly impaired proplatelet formation, a critical step in functional platelet production, through the inhibition of autocrine estradiol signaling in human megakaryocytes. Furthermore, we identified aromatase, an indispensable enzyme for estradiol biosynthesis, as a novel neo-substrate of cereblon. IMiDs promoted the recruitment of aromatase to cereblon, resulting in the degradation of aromatase in a proteasome-dependent manner. Finally, aromatase was significantly degraded in the bone marrow of patients with multiple myeloma who developed thrombocytopenia with IMiDs treatment. These data suggest that aromatase is a neo-substrate of cereblon that is responsible for IMiDs-induced thrombocytopenia.