The long noncoding RNA (lncRNA) HOTAIR acts in trans to epigenetically silence a 40-kb region of the HOXD gene cluster during development. In aggressive breast cancer, HOTAIR overexpression promotes metastasis, drug resistance, recurrence, and is a negative prognostic factor. However, the precise molecular mechanisms by which HOTAIR induces the formation of heterochromatin at specific sites in the genome to silence tumor suppressor genes remains widely unknown. To learn more about the molecular role of HOTAIR, we explored whether it was modified by the N6-methyladenosine RNA modification, which is dysregulated in breast cancer and has been proposed to play an essential role in gene repression by mediating lncRNA-protein interactions. Because we mapped m6A to a single nucleotide within the second domain of HOTAIR, we performed a quantitative proteomic analysis to identify additional HOTAIR-protein interactions that may be mediated by the post-transcriptional modification. We found that HOTAIR interacts with the YTH domain-containing protein 1 (YTHDC1), a member of a family of proteins known to recognize m6A residues. To determine the role of m6A in the HOTAIR-YTHDC1 interaction, we performed RNA pulldown assays with purified YTHDC1 and in vitro transcribed wild-type and m6A mutant HOTAIR in the presence or absence of methylation. Our data found that YTHDC1 preferentially interacts with wild-type methylated HOTAIR, suggesting that m6A mediates the HOTAIR-YTHDC1 interaction. However, it is not yet known if the m6A residue of HOTAIR recruits YTHDC1 to promote the transcriptional silencing of important suppressor genes. Thus, future research exploring the role of the m6A-mediated HOTAIR-YTHDC1 interaction in metastatic breast cancer will demonstrate whether a better understanding of the lncRNA can drive the development of breast cancer therapeutics. This is of utmost importance because invasive breast cancer remains a leading cause of death for women worldwide despite recent advancements in diagnosis and treatments.