Parkinson disease (PD) and multiple system atrophy (MSA) are neurodegenerative disorders characterized by the accumulation of alpha-synuclein. Distinguishing between these conditions remains a significant challenge. This study thus employed quantitative susceptibility mapping (QSM) to evaluate subcortical iron deposition and its clinical implications in patients with PD or MSA and a group of healthy controls (HCs).The study included 26 patients with MSA, 40 patients with PD, and 35 HCs. We used magnetic resonance imaging (MRI)-based QSM to measure iron accumulation in the substantia nigra pars compacta (SNc), substantia nigra pars reticulata (SNr), and globus pallidus internus (GPi). We assessed differences between groups, examined correlations with clinical scores, and conducted receiver operating characteristic (ROC) curve analysis.Compared to those with PD, patients with MSA showed more severe motor and nonmotor impairment. QSM analysis indicated a significant increase in iron levels in the SNc, SNr, and GPi regions in patient groups compared to HCs. In patients with MSA, a notable positive correlation was found between SNc QSM values and Non-Motor Symptoms Scale scores (r=0.4; P=0.043). In patients with PD, a positive association was observed between iron levels in the SNc and Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) (r=0.395; P=0.012) and Hamilton Depression Rating Scale scores (r=0.313; P=0.049). Furthermore, iron content in the GPi inversely correlated with rapid-eye movement sleep behavior disorder questionnaire-Hong Kong scores (r=-0.342; P=0.031). The SNr region demonstrated the best ability to discriminate between MSA and PD with an area under the curve (AUC) of 0.67, followed by the GPi (AUC =0.64) and SNc (AUC =0.57).QSM effectively quantified subcortical iron deposition in the PD, MSA, and HC groups. The correlations found between iron levels and clinical manifestations provide insights into the pathophysiological processes of these disorders, highlighting the potential of QSM as a diagnostic tool for differentiation.2024 Quantitative Imaging in Medicine and Surgery. All rights reserved.