Objective: To determine whether prolonged intrauterine device (IUD) usage is associated with decreased HOXA10 expression and increased methylation in the endometrium. Design: Observational study. Patient(s): Women wearing IUDs and not wearing IUDs. Intervention(s): Immunohistochemistry of HOXA10 and methylation-specific PCR. Main Outcome Measure(s): Endometrial HOXA10 expression levels and methylation frequency. Result(s): The IUD usage was associated with decreased endometrial HOXA10 expression, concordant with higher frequency of HOXA10 promoter hypermethylation. The HOXA10 hypermethylation was associated with the duration of IUD usage, irrespective age, gravidity, parity, and IUD type. Conclusion(s): Prolonged IUD use may induce endometrial HOXA10 hypermethylation and reduced expression. These results suggest a possible novel mode of action for IUD, a possibility to rectify the aberrant methylation through pharmacologic means, and a possible noninvasive way for detection of aberrant methylation at HOXA10. Copyright © 2010 American Society for Reproductive Medicine, Published by Elsevier Inc.