Abstract Repeated exposure to methamphetamine (MAP) results in a progressively enhanced and enduring behavioral response to the drug. This phenomenon is known as behavioral sensitization. MAP-induced sensitization has been suggested to underlie certain aspects of MAP psychosis and schizophrenia. The mesolimbic dopamine system including the ventral tegmental area, nucleus accumbens (NAc) and associated brain regions such as the amygdala (AMG) are proposed to be involved in the behavioral sensitization. However, the molecular mechanisms underlying this protracted alteration of behavior are almost unknown. Here we examined protein expression profiles in the AMG of acute MAP-treated and MAP-sensitized rats using 2-DE-based proteomics. Analysis revealed that 64 and 43 protein spots were differentially regulated in the AMG of acute MAP-treated and MAP-sensitized rats, respectively, when compared to control rats. A total of 48 and 34 proteins were identified in these two models, respectively using MALDI-ToF-MS. When the results were compared between acute and chronic MAP-treated groups, only 9 proteins were identified in common. These proteins could be related to acute MAP effects and/or non-specific effects. It is therefore suggested that AMG react differently to the acute and repeated administration of MAP at least at the protein expression level. A number of proteins in the categories of synaptic, cytoskeletal, oxidative stress, apoptosis, and mitochondria related proteins were differentially expressed in the AMG of sensitized animals. Changes of these protein expressions in the AMG could be associated with the mechanism underlying behavioral sensitization.