Increasing evidence suggests a relationship between oxidative stress and α-synuclein aggregation, the primary pathological hallmark of Parkinson disease (PD). However, a direct causal relationship has not yet been established in vivo in mouse models of PD. Superoxide dismutase 2 (SOD2) is rate limiting in the antioxidant machinery of the mitochondria and even its partial deficiency elevates oxidative stress in mice. Therefore, in order to investigate a possible interaction between oxidative stress and α-synuclein aggregation in vivo, a transgenic model of PD with haplodeficiency for SOD2 was generated on the basis of the well-characterized murine (Thy-1)-h[A30P]-α-synuclein transgenic line. In comparison with littermate controls with full SOD2 capacity, α-synuclein transgenic mice with partial SOD2 deficiency exhibited a significantly more advanced stage of synucleinopathy at 16 months, as demonstrated by higher median PK-PET blot scores (p < 0.01) and a greater amount of truncated α-synuclein in the insoluble fraction of homogenized brains (p < 0.05). These results show that compromising the capacity to scavenge free radicals can exacerbate α-synuclein aggregation, indicating that elevated levels of oxidative stress could modulate the progression of PD.