Serotonin syndrome (SS), a potentially life-threatening adverse drug reaction caused by excessive serotonergic agonism in central and peripheral nervous system serotonergic receptors, may be caused by a single drug or a combination of drugs with serotonergic activity. The syndrome results in a variety of mental, autonomic and neuromuscular changes, which can range in severity from mild to life-threatening. To our knowledge, we present the first reported case of SS associated with linezolid and methadone with a brief review of the literature.