Epidermal growth factor (EGF) has been proposed as a candidate biomarker for cognitive impairment in Parkinson's disease (PD). We aimed to assess the relationship between serum EGF and cognitive functions in early, drug-naive PD patients and evaluate the predictive value of EGF on cognitive functions in a 2-year follow-up study. Serum EGF was measured in 65 early, drug-naive PD patients, that underwent a comprehensive neuropsychological battery. Motor symptoms were assessed by means of the Unified Parkinson's Disease Rating Scale, Part III (UPDRS-III). Neuropsychological evaluation was repeated after 2 years. Spearman's rank correlation was used to assess the relationship between serum EGF levels and neuropsychological variables. Linear regression analysis was used to evaluate the relationship between EGF and neuropsychological scores as well as other variables (age, gender, UPDRS-III, levodopa equivalent dose, and type of treatment at follow-up) potentially affecting cognitive performance. Variation over time in cognitive scores was analyzed using repeated-measures ANOVA. At baseline, EGF was the only significant variable associated with performance on semantic fluency (R (2) = 0.131; p = 0.005). EGF levels (p = 0.025), together with UPDRS-III (p = 0.009) and age (p = 0.011), were associated with performance on frontal assessment battery (R (2) = 0.260). At 2-year follow-up, EGF was the only significant variable to predict performance on semantic fluency (R (2) = 0.147; p = 0.025) and color naming task of Stroop color-word test (R (2) = 0.121; p = 0.044). Serum EGF levels are related to frontal and temporal cognitive functions in early, drug-naive PD patients and predict performance on frontal and posterior cognitive functions at 2-year follow-up. EGF is proposed as a potential serum biomarker for early cognitive impairment in PD.