This retrospective study mainly analyzed the relationship between prostate tumor overexpressed 1 (PTOV1) and cytokeratin 19 fragment (Cyfra21-1) and neoadjuvant chemosensitivity in patients with lung adenocarcinoma (LUAC).A total of 110 LUAC patients who received neoadjuvant chemotherapy (cisplatin 75 mg/m2 combined with pemetrexed 500 mg/m2) from February 2022 to February 2024 were selected. They were divided into a chemoresistant group (n=32) and a chemosensitive group (n=78) based on treatment response, and their clinical data were analyzed. Serum levels of PTOV1 and Cyfra21-1 in both groups were measured using enzyme-linked immunosorbent assays for comparison. The association between PTOV1 and Cyfra21-1 and neoadjuvant chemosensitivity was evaluated, along with their predictive value for chemosensitivity in LUAC patients. Logistic multivariate regression analysis was conducted to further explore the factors influencing neoadjuvant chemosensitivity.Significant differences were observed between the chemoresistant and chemosensitive groups in age, distant metastasis, and tumor differentiation. The chemoresistant group showed significantly higher levels of PTOV1 and Cyfra21-1 compared to the chemosensitive group. Both PTOV1 and Cyfra21-1 were significantly correlated with neoadjuvant chemosensitivity, with an area under the curve of no less than 0.700 for predicting chemosensitivity in LUAC patients. Logistic regression analysis indicated that distant metastasis, differentiation status, PTOV1, and Cyfra21-1 were independent factors influencing neoadjuvant chemosensitivity in LUAC patients.PTOV1 and Cyfra21-1 are upregulated in LUAC patients who are resistant to neoadjuvant chemotherapy. Both markers not only have predictive value for chemosensitivity in these patients, but are also independent factors affecting neoadjuvant chemosensitivity.