Escalation of drug intake reliably occurs when animals are allowed extended self-administration access. As a form of plasticity, escalation of drug intake may be accompanied by neuroadaptive changes that are related to the transition from controlled use to addiction. The purpose of the present experiment was to examine the effects of agmatine (decarboxylated L-arginine) on the escalation of intravenous (iv) fentanyl and cocaine self-administration in rats. Subjects were allowed 12 h of daily access to fentanyl (2.5 microg/kg) or cocaine (0.2 mg/kg) under a fixed-ratio (FR) 1 schedule of reinforcement for 30 days. Animals self-administering fentanyl were distributed into three groups: (1) low-dose agmatine (10 mg/kg) throughout self-administration; (2) high-dose agmatine (30 mg/kg) throughout self-administration; and (3) high-dose agmatine after significant escalation (Day 18) of drug intake had occurred. Animals in a fourth group were pretreated with a high dose of agmatine throughout 30 days of cocaine self-administration. Both doses of agmatine, when given throughout self-administration, significantly decreased the escalation of responding that occurred for fentanyl but not cocaine. In the group that received agmatine after significant escalation had occurred, fentanyl-maintained responding was not significantly altered. These data indicate that agmatine attenuates the escalation of fentanyl self-administration if administered before the escalation begins and may mediate neuroadaptive events related to chronic opioid self-administration.