<p>Hemodialysis is an effective treatment option for acute caffeine intoxication. However, the efficacy of continuous renal replacement therapy remains a subject of debate. We encountered a case of acute caffeine intoxication that was managed using high-flow continuous hemodiafiltration. To evaluate the effectiveness of high-flow continuous hemodiafiltration, we compared it with other continuous renal replacement therapy approaches in managing cases of caffeine intoxication. In this study, we aimed to elucidate the caffeine-removal ability of continuous renal replacement therapy and assess its effectiveness. Additionally, we aimed to investigate the underlying reasons for the conflicting reports regarding the effectiveness of continuous renal replacement therapy. The time course of the blood caffeine concentration and elimination half-life were used for the evaluation. A woman in her 40s attempted suicide by ingesting an overdose of caffeine hydrate tablets. She presented with sweating, vomiting, tachycardia, sinus tachycardia, and tremors. The serum caffeine concentration in this case decreased from 103 to 50&#xa0;μg/mL after high-flow continuous hemodiafiltration. The initial symptoms at the time of admission also disappeared post-treatment. Caffeine clearance by continuous renal replacement therapy may vary depending on the blood caffeine concentration, and this concentration-dependent variation may lead to discrepancies in the evaluation of continuous renal replacement therapy. The discrepancies in the ongoing debate regarding the efficacy of continuous renal replacement therapy were likely attributable to the selection of inappropriate comparators. We inferred that continuous renal replacement therapy provides a therapeutic benefit because continuous renal replacement therapy may facilitate caffeine clearance.</p>