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Background: We aimed to examine whether patients with de novo and relapsed/progressed stage IIIB–IV non-small cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations have different prognoses. Methods: This retrospective study analyzed the Health Insurance Review and Assessment claims data in South Korea from 2013 to 2020. Patients with stage IIIB–IV NSCLC without EGFR or ALK mutations who received first-line palliative therapy between 2015 and 2019 were identified. Overall survival (OS), time to first subsequent therapy (TFST), and time to second subsequent therapy (TSST) were estimated using the Kaplan–Meier method. Multivariate Cox regression analysis was used to reveal the impact of de novo versus relapsed/progressed disease on OS. Treatment patterns, including treatment sequence, top five most frequent regimens, and time to treatment discontinuation, were described in both groups. Results: Of 14,505 patients, 12,811 (88.3%) were de novo, and 1,694 (11.7%) were relapsed/progressed. The median OS in the de novo group was 11.0 versus 11.5 months in the relapsed/progressed group (P = 0.002). The ongoing treatment probability was higher in relapsed/progressed patients than in de novo patients from 6.4 months since the initiation of first-line treatment (P < 0.001). Median TSST was shorter in the de novo group than in the relapsed/progressed group (9.5 vs. 9.9 months, P < 0.001). In multivariate analysis, de novo disease was associated with shorter OS (hazard ratio 1.07; 95% confidence interval 1.01–1.14). The overall treatment patterns for de novo and relapsed/progressed patients were similar. Conclusions: De novo patients had poorer OS and TSST after the initiation of palliative therapy than relapsed/progressed patients. These findings suggest that the stage of the disease at the time of initial diagnosis should be considered in observational studies and clinical trials as a prognostic factor. [ABSTRACT FROM AUTHOR]