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<b>Objective</b> The aim of this study was to test whether carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA21-1) can be used as a prognostic factor for non-small-cell lung cancer (NSCLC) after two cycles of adjuvant chemotherapy in NSCLC patients.<br><b>Methods</b> A total of 169 patients underwent at least two cycles of adjuvant chemotherapy. The serum levels of CEA and CYFRA21-1 were recorded after the second cycle of chemotherapy, and the patient follow-up was conducted. Overall survival (OS) and disease-free survival (DFS) were used as the primary endpoint and the secondary endpoint, respectively.<br><b>Results</b> The high levels of CEA and CYFRA21-1 after two cycles of adjuvant chemotherapy were poor prognostic factors for OS, with risk ratios (RR) of 2.003 and 1.702, respectively. A high CEA level was a poor prognostic factor (RR 1.152) for DFS. The median survival time (MST) of the high CEA level group was 26 months, whereas that of the normal group was 61 months (<i>P</i><0.0001). The median DFS time of the high CEA group and the normal group was 34 and 53 months, respectively (<i>P</i><0.0001). The MST of the high CYFRA21-1 group and the normal group was 43 and 56 months, respectively (<i>P</i><0.0001).<br><b>Conclusions</b> The high serum levels of CEA or CYFRA21-1 after two cycles of adjuvant chemotherapy are poor prognostic factors for NSCLC patients.