Symptoms caused by a selective serotonin reuptake inhibitor (SSRI) overdose are often mild and can be managed with supportive care and close monitoring, even when complicated by serotonin syndrome. There are limited pharmacokinetic data regarding massive overdoses of paroxetine, and the severity of an SSRI overdose is likely to be underestimated. We describe a fatal case of severe serotonin syndrome and acute respiratory distress syndrome (ARDS) following an overdose of controlled-release paroxetine. A 53-year-old male with depression presented with altered consciousness. He had ingested controlled-release paroxetine along with other medications. On arrival, he had ocular flutter and myoclonus, and blood examinations revealed acute kidney injury and rhabdomyolysis, which suggested serotonin syndrome. Computed tomography (CT) showed pharmacobezoars in the esophagus and stomach. Symptoms of serotonin syndrome and hypotension persisted despite administration of high doses of vasopressors with endotracheal intubation. We performed endoscopic decontamination to remove pharmacobezoars from the stomach. Finally, he developed severe ARDS and died due to respiratory failure on day 23. Sequential serum concentrations of paroxetine were 5.38 µg/mL at admission and 3.21 µg/mL on day 7, both above lethal levels. This case highlights the potential for fatal complications and prolonged toxicity in the case of a massive overdose of controlled-release paroxetine. We should recognize that such an overdose may be lifethreatening and should consider aggressive interventions including endoscopic decontamination. A better understanding of the pharmacokinetics of a massive SSRI overdose would be helpful for optimal management.