Serotonin syndrome is a potentially lethal adverse drug reaction that may occur in patients taking proserotoninergic medications. Drug interactions are often responsible for the causation of this syndrome. We report two cases of severe serotonin syndrome induced by the administration of cyclobenzaprine in postoperative patients already receiving another proserotoninergic drug (phenelzine in one case and duloxetine in the other). In both cases, symptoms of autonomic instability and severe agitation started within hours of initiation of cyclobenzaprine and fully resolved within 3 days after discontinuing the proserotoninergic drugs. We conclude that cyclobenzaprine should be used with extreme caution in patients receiving other serotonin-enhancing drugs; these patients should be closely monitored for manifestations of serotonin syndrome.