Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. The purpose of this study was to analyze the profile of the tear proteome of patients with idiopathic PD (iPD), carriers of the E46K-SNCA mutation and healthy subjects (CT) and to identify biomarkers for the early diagnosis of PD. An observational, prospective and case-control pilot study was carried out in 24 patients with iPD, 3 carriers of the E46K-SNCA mutation and 27 CT subjects. The patients' neurological involvement was scored and their tear samples were analyzed using nano-liquid chromatography-mass spectrometry (nLC-MS/MS). These analyses led to the identification of 560 tear proteins in which some of the deregulated proteins were involved in immune response, apoptosis, collagen degradation, protein synthesis, defense and altered lysosomal function. Of these proteins, six related to neurodegenerative processes, showed a good capacity to classify patients and controls. These findings revealed that some proteins were upregulated in the tears of PD patients, mainly those involved in lysosomal function. It is worth highlighting the importance of this study in identifying tear proteins implicated in neurodegeneration and its relationship with PD patients with an aggressive disease phenotype.