Neoadjuvant immune checkpoint blockade (ICB) outperforms adjuvant ICB for treatment of stage IIIB-D melanoma, but potential biomarkers of response, such as interferon-gamma (IFNγ) signature and tumor mutational burden (TMB), are insufficient. Preclinical studies suggest that emotional distress (ED) can negatively affect antitumor immune responses via β-adrenergic or glucocorticoid signaling. We performed a post hoc analysis evaluating the association between pretreatment ED and clinical responses after neoadjuvant ICB treatment in patients with stage IIIB-D melanoma in the phase 2 PRADO trial ( NCT02977052 ). The European Organisation for Research and Treatment of Cancer scale for emotional functioning was used to identify patients with ED (n = 28) versus those without (n = 60). Pretreatment ED was significantly associated with reduced major pathologic responses (46% versus 65%, adjusted odds ratio 0.20, P = 0.038) after adjusting for IFNγ signature and TMB, reduced 2-year relapse-free survival (74% versus 91%, adjusted hazard ratio 3.81, P = 0.034) and reduced 2-year distant metastasis-free survival (78% versus 95%, adjusted hazard ratio 4.33, P = 0.040) after adjusting for IFNγ signature. RNA sequencing analyses of baseline patient samples could not identify clear β-adrenergic- or glucocorticoid-driven mechanisms associated with these reduced outcomes. Pretreatment ED may be a marker associated with clinical responses after neoadjuvant ICB in melanoma and warrants further investigation. ClinicalTrials.gov registration: NCT02977052 .