Background/objectives: Alpha-synuclein (aSyn) is best known for its role in Parkinson's disease. Increasing evidence suggests a bidirectional relationship between diabetes mellitus and synuclein pathology. Carboxymethyllysine (CML), an advanced glycation end-product, serves as a marker of cumulative glycation stress and tissue damage in diabetes. Our study aimed to evaluate epidermal phosphorylated alpha-synuclein at Ser129 (p-aSyn) immunoreactivity in relation to CML accumulation in epidermis. Methods: Skin punch biopsies were obtained from seven diabetic patients with long-standing type 2 diabetes (T2DM), and from seven healthy volunteers. Tissue samples were processed and analyzed by immunohistochemical DAB-staining for p-aSyn and CML. Quantitative analysis was performed by measuring the percentage area of positive staining using Fiji/ImageJ2. Integrated density was also assessed as a complementary threshold-limited measure of staining signal intensity. Statistical analysis and data visualization were conducted using GraphPad Prism. Comparisons between groups were performed using the exact two-tailed Mann-Whitney U test. Results: Area-fraction analysis showed significantly greater CML-positive staining in diabetic epidermis than in controls (median 10.18 vs. 8.955, p = 0.0262), whereas p-aSyn-positive area fraction did not differ significantly between groups (13.53 vs. 14.64, p = 0.8048). In the complementary integrated density analysis, p-aSyn signal was significantly higher in diabetic epidermis than in controls (21,365 vs. 10,960, p = 0.0023), whereas the increase in CML integrated density did not reach statistical significance (14,165 vs. 6585, p = 0.1282). In diabetic epidermis, both markers showed a more widespread distribution, involving basal keratinocyte cytoplasm and extension into suprabasal layers. Control samples showed staining largely restricted to basal cell contours. In serial sections, p-aSyn and CML showed a similar topographic distribution in diabetic skin. Conclusions: These preliminary observations suggest that chronic diabetic skin changes are associated with increased epidermal CML burden when assessed by area fraction and with higher p-aSyn signal intensity when assessed by integrated density. However, because the study was small and based on semiquantitative DAB immunohistochemistry, the findings should be interpreted cautiously and require validation in larger multimodal studies.