Whether early medication reconciliation and integration can reduce polypharmacy and potentially inappropriate medication (PIM) in the emergency department (ED) remains unclear. Polypharmacy and PIM have been recognized as significant causes of adverse drug events in older adults. Therefore, this pilot study was conducted to delineate this issue. An interventional study. A medical center in Taiwan. Older ED patients (aged ≥65 years) awaiting hospitalization between December 1, 2017, and October 31, 2018 were recruited in this study. A multidisciplinary team and a computer-based and pharmacist-assisted medication reconciliation and integration system were implemented. The reduced proportions of major polypharmacy (≥10 medications) and PIM at hospital discharge were compared with those on admission to the ED between pre- and post-intervention periods. A total of 911 patients (pre-intervention = 243 vs post-intervention = 668) were recruited. The proportions of major polypharmacy and PIM were lower in the post-intervention than in the pre-intervention period (-79.4% vs -65.3%; P < .001, and - 67.5% vs -49.1%; P < .001, respectively). The number of medications was reduced from 12.5 ± 2.7 to 6.9 ± 3.0 in the post-intervention period in patients with major polypharmacy (P < .001). Early initiation of computer-based and pharmacist-assisted intervention in the ED for reducing major polypharmacy and PIM is a promising method for improving geriatric care and reducing medical expenditures. J Am Geriatr Soc 67:2298-2304, 2019.