Trimetazidine is contraindicated in movement disorders, however, a not negligible part of trimetazidine users is still patients with Parkinson's disease (PD). The present study aimed to objectively determine the impact of trimetazidine on the severity of symptoms and the health-related quality of life of patients with PD by measuring changes after its withdrawal. A consecutive series of 42 patients with PD using trimetazidine underwent detailed neurological and neuropsychological assessments at baseline and three months after the discontinuation of trimetazidine. Clinically relevant improvements were achieved with discontinuation of trimetazidine according to changes in scores of each part of the Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale (Part I: -25.7%, p < 0.001; Part II: -23.8%, p < 0.001; Part III: -28.5%, p < 0.001; Part IV: -30.1%, p = 0.004) and total scores of the Non-Motor Symptoms Scale (-25.6%, p = 0.004) and the Montgomery-Asberg-Depression Rating Scale (-20.1%, p = 0.001). Benefits resulting from the withdrawal of the drug also manifested in the improvement of the health-related quality of life based on changes in the summary index of the 39-item Parkinson's Disease Questionnaire (-18.2%, p = 0.031). Our results provide clinical rationale for strictly avoiding the use of trimetazidine in PD. Discontinuation of trimetazidin results in clinically relevant improvements in Parkinsonian symptoms.