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This open-labeled and comparative study aimed to test the efficacy and safety of a fermented rice extract-based substance containing yeast-fermented powder having aldehyde dehydrogenase (KisLip^®, Pico Entech, Republic of Korea) in healthy male individuals. Healthy male subjects (n = 20) consumed 90 g of alcohol at their first visit. At the second visit, participants consumed 90 g of alcohol or alcohol with a low dose of KISLip^® (2000 mg, KL-L) and then 90 g of alcohol or alcohol with a high dose of KISLip^® (3000 mg, KL-H) at the third visit. The efficacy of KISLip^® depends on the mutational status of important genes related to alcohol metabolism, including alcohol dehydrogenase (<i>ADH1B</i>), cytochrome P4502E1 (<i>CYP2E1</i> (<i>5B</i>) and <i>CYP2E1</i> (<i>6</i>)), and aldehyde dehydrogenase (<i>ALDH2</i>). KISLip^® significantly reduced the highest level (Cmax) of alcohol and overall levels of acetaldehyde compared to the alcohol-only group in a dose-dependent manner. These significant effects of KISLip^® on alcohol metabolism were observed independent of mutations in the four genes. In addition, hangover symptoms were significantly decreased in the KISLip^® treated groups. During the study, the participants did not show any adverse events after KISLip^® intake. This clinical study suggested that supplementation of KISLip^® had beneficial effects on alcohol metabolism and might ameliorate the severity of hangovers without any adverse events.