The selective estrogen receptor downregulator (SERD) fulvestrant can be used as second line treatment in patients relapsing after treatment with tamoxifen, a selective estrogen receptor modulator (SERM). Unlike tamoxifen, SERDs are devoid of partial agonist activity. While the full antiestrogenicity of SERDs may result in part from their capacity to down-regulate levels of estrogen receptor alpha (ERα) through proteasome-mediated degradation, SERDs are also fully antiestrogenic in the absence of increased receptor turnover in HepG2 cells. Here we report that SERDs induce a rapid and strong SUMOylation of ERα in ERα-positive and -negative cell lines including HepG2 cells. Four sites of SUMOylation were identified by mass spectrometry analysis. In derivatives of the SERD ICI164,384, SUMOylation was dependent on the length of the side chain and correlated with full antiestrogenicity. Preventing SUMOylation by overexpression of a SENP desumoylase partially derepressed transcription in the presence of full antiestrogens in HepG2 cells without a corresponding activity increase in the presence of agonists or of the SERM tamoxifen. Mutations increasing transcriptional activity in the presence of full antiestrogens reduced SUMOylation levels and suppressed stimulation by SENP1. Our results indicate that ERα SUMOylation contributes to full antiestrogenicity in the absence of accelerated receptor turnover.