It is essential to develop animal models to study the role of genetic factors in the relapse of drug-seeking behavior in genetically engineered mutant mice. This paper reports a typical model of drug-primed and cue-induced reinstatement of extinguished methamphetamine (METH)-seeking behavior in mice. C57BL/6J mice were trained to self-administer METH (0.1mg/kg/infusion) by poking their nose into an active hole under a fixed ratio schedule in daily 3-h sessions. After acquiring stable METH self-administration behavior, the mice were subjected to extinction training in the absence of both METH and METH-associated cues. Once the active nose-poking responses were extinguished, drug-primed and cue-induced reinstatement were investigated according to a within-subjects design. A priming injection of METH reliably reinstated the extinguished drug-seeking behavior in the absence of both METH and METH-associated cues. Interestingly, the drug-primed METH-seeking behavior disappeared within 2 months after withdrawal from METH, while cue-induced reinstatement of extinguished METH-seeking behavior lasted for at least 5 months after the withdrawal. A correlation study revealed that drug-primed, but not cue-induced, reinstatement behavior was positively correlated with the total amount of METH taken by individuals during METH self-administration. In conclusion, our findings suggest that the present reinstatement procedure for mouse model of relapse is useful and reliable, and different neural mechanisms may be involved in drug-primed and cue-induced METH-seeking behavior.