The study was to investigate whether immunoproteasome (i-proteasome) and its downstream pathway are related to the pathogenesis of Parkinson's disease (PD). Rats were treated with rotenone showed significant weight loss and dyskinesia, which is consistent with the degeneration of TH-positive neurons and the activation of Iba-1-positive microglia/macrophages. Two major catalytic subunits of i-proteasome (PSMB9 and PSMB8) were seldom expressed in rat substantia nigra (SN) under normal condition, but they were significantly up-regulated with the release of TNF-α and IFN-γ after exposure to rotenone. In addition, compared with control group, the antigen presentation-related proteins antigen peptide transporter (TAP) 1, TAP2, major histocompatibility complex (MHC)-I and MHC-II levels were significantly up-regulated in rotenone group, which was in line with the accumulation of α-syn. These findings suggested that i-proteasome and antigen presentation pathways (related proteins) were upregulated by rotenone in a PD rat model.