Abstract Contradictory evidence exists regarding the nature and degree of impaired cognitive flexibility in PD. Dopaminergic medication may be expected to ameliorate such cognitive deficits, yet both medicated and unmedicated patients have been reported to perform more poorly than control subjects on tasks of cognitive flexibility, suggesting that such deficits may also be affected by other disease-related variables. The present study examined whether asymmetric dopamine deficiency (revealed by unilateral symptom onset) is related to the performance of spontaneous and reactive flexibility in PD, and the possible interaction of dopaminergic medication with such asymmetry. Thirty-five PD patients with mild motor symptoms and unilateral onset of PD (left-onset = 14; right-onset = 21) performed the Alternate Uses (AU) and intradimensional/extradimensional shift (IED) tasks. Interaction between side of onset and medication was observed for the number of errors in the AU task and number of reversal errors in the IED task. Significantly more AU errors were made by medicated patients with left-onset, as compared to all other participants. Conversely, medicated patients with right-onset made the most reversal errors. These results suggest that relatively early in the disease process when dopamine deficit in the less-affected hemisphere is mild, optimal dopaminergic medication (with respect to motor function) may involve over-medication of the less-affected hemisphere. Thus, AU errors may be the consequence of hyperdopaminergic state leading to impaired functioning of the left hemisphere, whereas increased reversal errors in right-onset PD patients receiving dopaminergic medication is related to impaired dopamine function in the right hemisphere.