OBJECTIVE Self-injurious behavior (SIB) affects 0.8 to 10% of individually housed non-human primates, and is a substantial threat to their health and well being. The potential for SIB to involve multiple neurotransmitters and the complex variations in response to external stressors complicate case management. Modulation of the adrenergic system by use of guanfacine, an alpha2A-adrenergic receptor agonist, was assessed as a novel therapeutic strategy for SIB. METHODS The efficacy of guanfacine against SIB was evaluated in 11 self-biting episodes among two rhesus macaques (Macaca mulatta) and one baboon (Papio cynocephalus anubis). Affected animals were given guanfacine IM or PO at 0.5 mg/kg of body weight twice daily (rhesus) or 0.3 mg/kg (baboon) for 5 to 10 days, followed by gradual reduction of the dose to 0.25 mg/kg (rhesus) or 0.15 mg/kg (baboon) once daily over an average of 33 days. RESULTS The 0.5 mg/kg twice daily regimen of guanfacine halted all self-biting, whereas reducing the dose to 0.25 mg/kg given twice daily or 0.5 mg/kg given once daily resulted in reversion to self-biting in four of the 11 episodes. Recurrence was controlled by returning to twice daily 0.5 mg/kg dosing for one aggressive episode, and resolved in the three milder episodes without dose or frequency being increased. Self-biting after discontinuation of therapy recurred six times over five years in case 1, three times over 1.5 years in case 2, and three times over one year in case 3. Clinical assessment suggested that guanfacine therapy decreased agitation without overt side effects associated with alpha2-agonists, such as profound sedation. CONCLUSIONS The mechanism for guanfacine inhibition of self-biting is unclear, but could result from strengthening of prefrontal cortex inhibitory functions. Guanfacine therapy provides an effective psychological stabilizing tool that alleviates self-biting, and provides time to assess and address external stressors and triggers.