<b><i>Objective:</i></b> Chronic inflammatory processes contribute to the eventual death of motor neurons and the development of symptoms in both idiopathic Parkinson disease (PD) and multiple system atrophy (MSA). Given the faster rate of progression and more severe symptoms associated with MSA, we hypothesized that markers of inflammation would be more evident in the peripheral blood of MSA than PD patients, and that evidence of this inflammation might assist early diagnosis of MSA versus PD. <b><i>Methods:</i></b> We performed multiplex analysis to determine the concentrations of 37 immune-associated cytokines and chemokines isolated from the plasma of patients with PD (<i>n</i> = 25) and MSA (<i>n</i> = 14) and compared our results to those of age-matched controls (<i>n</i> = 15). We then applied a mixed-effect multiple regression model to determine if the concentration of cytokines in the plasma of patients with PD and MSA changed significantly over time. <b><i>Results:</i></b> Patients with MSA had a trend towards overall lower levels of immune-associated cytokines, while serum cytokine levels were increased in patients with PD. Statistically adjusted comparisons of overall changes in cytokine concentrations between the PD and MSA groups revealed higher concentrations of T-cell-associated cytokines TNFβ and IL-7 in PD. Comparison of samples taken over time revealed significantly faster rates of change in 4 different cytokine concentrations (IL-4, IL-15, IL-2, and IL-9) in patients with MSA versus patients with PD. <b><i>Conclusions:</i></b> Our results suggest that single measurements of plasma concentrations of inflammation-associated cytokines cannot be used to distinguish disease states. However, measurements made over time may correlate with pathogenesis. The significant changes in T-cell-associated cytokines may shed light on immune mechanisms that contribute to PD and MSA disease progression.