Abstract Background: Lichen simplex chronicus is a dermatological condition due to excessive scratching, with few studies on psychoneuroimmunology. Objective: We aimed to estimate the levels of stress, depression, and anxiety, and to measure serum levels of neurotrophins in patients with lichen simplex chronicus, and to correlate these parameters with the severity of the disease and pruritus. Methods: Thirty-six patients with lichen simplex chronicus and 36 age- and sex-matched healthy controls were included. Each participant was administered the Hospital Anxiety and Depression Scale and Perceived Stress Scale questionnaires, along with a visual analog scale for pruritus. Levels of neurotrophins (brain-derived neurotrophic factor, neurotrophin-3, nerve growth factor, glial cell line-derived neurotrophic factor) were determined by ELISA assays. Results: The scores of Perceived Stress Scale-10, Hospital Anxiety and Depression Scale were statistically higher in patients (p < 0.05 for all). The serum levels of all neurotrophins were significantly lower in patients compared to healthy controls (p < 0.05 for all). Disease severity showed no correlation with all four neurotrophins. In linear regression models applied for increased visual analog scale-pruritus scores and disease severity these two variables were statistically significant predictors (p = 0.043). Study limitations: A direct causal relationship was not addressed. Conclusion: Lichen simplex chronicus patients are at risk of increased levels of stress, anxiety, depression, and present decreased levels of neurotrophins, that may suggest a role in the pathophysiology of this disorder.