Background: The dopamine transporter (DaT) PET ligand [¹⁸F]FE-PE2I is used to aid the diagnosis of Parkinson’s disease. After encountering four patients with a history of daily sertraline use, who all showed atypical findings on [¹⁸F]FE-PE2I PET, we suspected that the selective serotonin reuptake inhibitor (SSRI), sertraline, might interfere with the results and lead to globally reduced striatal [¹⁸F]FE-PE2I binding due to sertraline’s high affinity for DaT. Methods: We rescanned the four patients with [¹⁸F]FE-PE2I PET after a 5-day sertraline pause. Sertraline plasma concentration was estimated based on body weight and dose, and specific binding ratios (SBR) in caudate nucleus, known to be more preserved in Parkinson’s, were used to estimate the effect on tracer binding. Comparison was made to a patient with [¹⁸F]FE-PE2I PET before and after a 7-day Modafinil pause. Results: We found a significant effect of sertraline on caudate nucleus SBR (p = 0.029). The effect showed a linear dose-dependent relationship that corresponds to a reduction in SBR by 0.32 or 0.44 for a 75 kg male or a 65 kg female, respectively, taking a daily dose of 50 mg sertraline. Conclusion: Sertraline is one of the most commonly used antidepressants and in contrast to other SSRI’s, sertraline show high affinity for DaT. We recommend that sertraline treatment is taken into account when patients are undergoing [¹⁸F]FE-PE2I PET especially in patients showing apparent globally reduced PE2I binding. If tolerable, pausing of the sertraline treatment should be considered, especially for doses above 50 mg/day.