Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFα, 0.25 mg/kg, i.p.) injection was administered in adult wild‐type mice and in mice lacking TNFα receptors (TNF R1/R2^−/−) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFα increase that remained elevated for 10 months, while peripheral TNFα (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNFα and LPS administration activated microglia and increased expression of brain pro‐inflammatory factors (i.e., TNFα, MCP‐1, IL‐1β, and NF‐κB p65) in wild‐type mice, but not in TNF R1/R2^−/− mice. Further, LPS reduced the number of tyrosine hydroxylase‐immunoreactive neurons in the substantia nigra (SN) by 23% at 7‐months post‐treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNFα, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro‐inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self‐propelling nature of Parkinson's disease. © 2007 Wiley‐Liss, Inc.