Background: Metaxalone is a centrally acting muscle relaxant with an unclear mechanism of action; it causes central nervous system depression and may affect polysynaptic spinal reflexes. In the literature, overdose is primarily characterized by sedation. Limited case reports describe serious toxicity. We report three cases of isolated metaxalone overdose characterized by muscular rigidity, tachycardia, and altered mental status (AMS). Seizures were reported in the pediatric ingestion and one adult patient exhibited hyperthermia. Case reports: Case One: A 61-year-old female presented to the emergency department (ED) 3 hours after ingesting 56 grams of metaxalone. She was hypertensive, (blood pressure (BP) 189/97), tachycardic, tachypneic, and had excess secretions. She was then intubated and sedated with a midazolam infusion, with a maximum rate of 12 mg/hr. Her body temperature (T) was 101° Fahrenheit (F) and muscle rigidity was noted. Her T peaked at 104 ° F. 13 hours post-ingestion her muscle rigidity had abated, her heart rate (HR) was improved to 80, and T decreased to 100.7 ° F. 24 hours postingestion she was extubated and admitted to taking only metaxalone. Case Two: A 14-month-old male was brought to the ED after ingesting 1600mg metaxalone. 2 hours post-ingestion the child was ataxic and acting strangely. At 4 hours post-ingestion the child had mydriasis, trismus, stiff legs, and a seizure, so was given a dose of lorazepam. He was hypertensive and tachycardic (HR 160). He had a second seizure and was again given lorazepam. Muscle rigidity resolved at 8 hours post-ingestion, however, he remained drowsy, and ataxic with mydriasis. He was discharged on hospital day 2. Case Three: A 41-year-old female presented to the ED 1 hour post-ingestion of 16 grams metaxalone. 6 hours post-ingestion she developed AMS, muscle rigidity, clonus, mydriasis, tachycardia (HR 120). She became hypotensive, requiring fluid resuscitation. Due to altered mental status she was intubated and sedated with midazolam. Muscle rigidity, AMS and diaphoresis persisted until 36 hours post-ingestion. Electroencephalogram was normal. Creatinine kinase peaked at 13,571 units/liter. She was medically cleared 60 hours post ingestion. Discussion: Metaxalone overdoses are generally well tolerated and respond to supportive care. However, the above cases demonstrate that metaxalone overdose may have significant neuromuscular and autonomic symptoms, which may mimic neuroleptic malignant syndrome or serotonin syndrome. Conclusion: Health care providers should be cognizant of the potential effects of metaxalone and ensure patients are monitored for an adequate period of time following overdose.