Neurological complications of Lyme disease include meningitis, encephalitis, dementia, and, rarely, parkinsonism. We present a case of striatonigral degeneration, a form of multiple system atrophy, in Lyme-associated parkinsonism. A 63-year-old man presented with erythema migrans rash, joint pains, and tremors. Serum and cerebrospinal fluid antibodies and polymerase chain reaction for Borrelia burgdorferi were positive. Clinical parkinsonism was diagnosed by several neurologists. Despite treatment, the patient continued to decline, with progressive disability, cognitive dysfunction, rigidity, and pulmonary failure. At autopsy, the brain showed mild basal ganglia atrophy and substantia nigra depigmentation, with extensive striatal and substantia nigral neuronal loss and astrogliosis. No Lewy bodies were identified; however, ubiquitin-positive glial cytoplasmic inclusions were identified in striatal and nigral oligodendroglia. There were no perivascular or meningeal infiltrates, the classic findings of neuroborreliosis. To our knowledge, this is the first report of striatonigral degeneration in a patient with B burgdorferi infection of the central nervous system and clinical Lyme-associated parkinsonism.