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This study investigates the expression features of serum lactate dehydrogenase (LDH) in patients with large cell neuroendocrine carcinoma of the lung (LCNEC) and evaluates its clinical prognostic significance. A prospective cohort study was conducted, enrolling 80 LCNEC patients admitted between January 2022 and January 2024 (case group) and 80 healthy individuals undergoing medical check-ups during the same period (control group). Serum LDH levels were quantitatively measured by enzyme-linked immunosorbent assay (ELISA). Independent risk factors for poor prognosis were analyzed using a Multifactorial Logistic Regression (MLR) model. The prognostic predictive capability of LDH was assessed with the receiver operating characteristic (ROC) curve. Serum LDH levels in the case group were notably higher than those in the control group (p < 0.05). Subgroup analysis revealed that LDH levels of patients with tumor maximum diameter ≥5 cm, low variation, stage III-IV, and lymph node metastasis were significantly higher than those of the equivalent reference groups (all p < 0.05). The poor prognosis group had higher LDH expression levels and lymph node metastasis rates compared to the good prognosis group (both p < 0.05). MLR revealed that LDH (OR = 2.130, 95% CI: 1.312-3.465) and lymph node metastasis were autonomous predictors of poor prognosis (both p < 0.05). ROC analysis indicated that LDH predicted prognosis with an AUC of 0.825 (95% CI: 0.752-0.898), an optimal critical value of 280.5 U/L, a sensitivity of 75.0%, and a specificity of 78.0%. Serum LDH levels were abnormally elevated in LCNEC patients and significantly correlated with tumor malignancy features, which can act as a valid biological marker for assessing disease prognosis.