Serotonin syndrome (SS)/ serotonin toxicity/serotonin toxidrome may be a life-threatening condition that can develop within hours to days after starting serotonergic drugs. There is wide clinical spectrum of its severity, ranging from mild illness to very severe life-threatening illness. It is caused by the increased serotonin or 5hydroxytryptamine (5HT) activity in the central nervous system resulting in increased activation of serotonergic receptors mainly 5HT2A and 5HT2B. This usually occurs due to a serotonergic drug overdose or the simultaneous use of two or more serotonergic antidepressants. It may get precipitated even after the single dose administration of SSRI, as happened in our case. (1) The classical presentation includes hyperthermia, hyperreflexia, clonus and muscular rigidity. Some of these symptoms may be masked in a critically ill patient who is on mechanical ventilator with sedatives and muscle relaxants, making diagnosis challenging in such settings. In this case report serotonin syndrome is diagnosed with high index of suspicion and as a diagnosis of exclusion. Patient presented to us with history of benzodiazepine and insulin overdose. After initial stabilization in first three days, he was advised Escitalopram 10 mg by psychiatrist. Patient developed very high fever of 106-degree F, the very next day. After ruling out infectious and other non-infectious causes of fever swiftly and on the basis of Hunters criteria, diagnosis of SS was established in our case. Critical care physician is supposed to be aware of this entity and keep this diagnosis in their differential diagnosis in patients who are on SSRI and develop hyperthermia or acute mental status changes even after few hours of initiation of SSRI.