The psychostimulant methamphetamine is an addictive drug of abuse. The neuropeptide oxytocin has been shown to modulate methamphetamine-related reward and methamphetamine-seeking behaviour. Recent findings have implicated the nucleus accumbens core (NAcc) and subthalamic nucleus (STh) as key substrates involved in oxytocin modulation of acute methamphetamine-induced reward. It is not known, however, if oxytocin acts in these regions to reduce relapse to methamphetamine-seeking behaviour, and if this is through the oxytocin receptor. We aimed to determine whether oxytocin pretreatment into either the NAcc or STh would reduce relapse to methamphetamine use and if this could be reversed by co-administration of the oxytocin receptor antagonist desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT using a reinstatement model of self-administration. Male Sprague Dawley rats underwent surgery for the implantation of a jugular vein catheter and bilateral microinjection cannulae into the NAcc or STh under isoflurane anaesthesia. After recovery, rats were trained to self-administer intravenous methamphetamine (0.1mg/kg/infusion) by lever press during 2-hour fixed ratio 1 scheduled sessions for 20 days. Following extinction of lever press activity, the effect of microinjecting vehicle, oxytocin (NAcc: 0.5 pmol, 1.5 pmol, 4.5 pmol/side; STh: 0.2 pmol, 0.6 pmol, 1.8 pmol, 3.6 pmol), or co-administration of oxytocin (NAcc: 1.5 pmol/side; STh: 3.6 pmol/side) and desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT (NAcc: 1 nmol, 3 nmol; STh: 3 nmol) in the NAcc (500 nl/side) or STh (200 nl/side) on methamphetamine primed (1 mg/kg i.p.) reinstatement was examined. Our results showed that oxytocin administration into the NAcc decreased methamphetamine-induced reinstatement in a dose-dependent manner. In the STh, oxytocin reduced reinstatement to methamphetamine-seeking behaviour at the highest dose administered. In both regions, desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT partially reversed lever press activity to that exhibited by the control methamphetamine condition. These findings demonstrate that oxytocin modulation of the NAcc and STh is an important mediator of relapse to methamphetamine abuse.