Emerging evidence highlights a possible interplay between serum lipid profiles and Parkinson’s disease (PD), but the biological underpinnings remain largely unexplored. In this cross-sectional study, we investigated whether serum lipid levels (total cholesterol, high-density lipoprotein cholesterol (HDL), non-high-density lipoprotein cholesterol, and triglycerides) were associated with clinical severity and cerebrospinal fluid (CSF) biomarkers in early-stage PD patients. A cohort of 90 PD patients and 74 matched controls underwent serum lipid and CSF biomarker assessment and APOE genotyping. While serum lipid levels did not differ significantly between groups, PD patients showed reduced CSF α-synuclein. Notably, higher HDL levels correlated with higher CSF α-synuclein and amyloid-β42 (Aβ42) concentrations and milder motor impairment, independent of APOE ε4 status. APOE ε4 carriers displayed increased CSF phosphorylated tau and reduced Aβ42/Aβ40 ratio, but APOE genotype did not modify the observed HDL associations. These findings suggest that higher circulating HDL levels are associated with a milder clinical phenotype and a more favorable CSF biomarker profile in early-stage PD, potentially reflecting a protective role independent of APOE genotype. Further studies are warranted to validate these observations and to assess their therapeutic implications.