L-Dopa-induced dyskinesia (LID) is associated with the upregulation of striatal ∆FosB in animal models and patients with Parkinson's disease (PD). A mechanistic role of ∆FosB is suspected because its transgenic overexpression leads to the early appearance of LID in rodents and primates. This study in rodents is aimed at exploring the therapeutic potential of striatal ∆FosB gene suppression to control LID in patients with PD. To determine the effect of reducing striatal ∆FosB expression, we used RNAi gene knockdown in a rat model of PD and assessed abnormal involuntary movements (AIMs) in response to L-Dopa. Rats with dopamine depletion received striatal injections of rAAV-∆FosB shRNA or a control virus before exposure to chronic L-Dopa treatment. The development of AIMs during the entire L-Dopa treatment period was markedly inhibited by ∆FosB gene knockdown and its associated molecular changes. The antiparkinsonian action of L-Dopa was unchanged by ∆FosB gene knockdown. These results suggest a major role for ∆FosB in the development of LID and support exploring strategies to reduce striatal ∆FosB levels in patients with PD.