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Hybrid reactive-extractive distillation (RED) has been popular for separating azeotropic mixtures, as it combines the chemical reaction and physical azeotropic separation in a single unit operation. At least 18 studies have been published between 2020 and 2023, all of them relying on the hydration of ethylene oxide (EO) to form ethylene glycol (EG), without considering the potential side reactions that could impact the RED performance. This study shows one possible scenario where the formation of higher-level glycols during side reactions has led to significant increases in the total energy consumption and the total annual cost (TAC) by about 839 and 154%, respectively. These increases were due to the larger column size, low operating pressure, and more expensive cooling refrigerant. Hence, the performance of RED may not be as favorable as previously reported, and side reactions can significantly reduce its effectiveness. Future RED studies must consider the potential side reactions.