Estrogen Receptor (ER) is an important target for pharmaceutical design. Like other ligand-dependent transcription factors, hormone-binding regulates ER transcriptional activity. Nevertheless, the mechanisms by which ligands enter and leave ERs and other nuclear receptors (NRs) remain poorly understood. Here, we report results of locally enhanced sampling (LES) Molecular Dynamics (MD) simulations to identify dissociation pathways of two ER ligands (the natural hormone 17-estradiol, E₂, and the selective estrogen receptor modulator (SERM) Raloxifene, RAL) from the hER ligand binding domain (LBD) in monomeric and dimeric forms. E₂ dissociation occurs via three different pathways in ER monomers. One resembles the "mouse-trap" mechanism (Path I), involving repositioning of H12, others involve the separation of H8 and H11 (Path II), and a variant of this pathway at the bottom of the LBD (Path II'). RAL leaves the receptor through Path I and a Path I variant in which the ligand leaves the receptor through the loop region between H11 and H12 (Path I'). Remarkably, ER dimerization strongly suppresses Paths II and II' for E₂ dissociation and modifies RAL escape routes. We propose that differences in ligand release pathways detected in the simulations for ER monomers and dimers provide an explanation for previously observed effects of ER quaternary state on ligand dissociation rates and suggest that dimerization may play an important, and hitherto unexpected, role in regulation of ligand dissociation rates throughout the NR family.