BACKGROUND: Serum carcinoembryonic antigen (CEA) and the soluble fragment of cytokeratin 19 (CYFRA 21-1) are supposed to have a prognostic role in patients with nonsmall cell lung cancer (NSCLC) after surgery, but it has not been used as an adjunct to the tumor-node-metastasis (TNM) staging system to provide therapy options for patients with pathological Stage I NSCLC. This study was designed to investigate the effect of serum levels of CEA and CYFRA 21-1 before and after surgery on the prognosis of patients with Stage I NSCLC. MATERIALS AND METHODS: A retrospective review was performed regarding the medical records and follow-ups of 169 patients with Stage I NSCLC before and after surgery. The patients were divided into three groups based on levels of serum CEA and CYFRA 21-1 before and after surgery: (1) continuously normal-level groups (CEA [NN] and CYFRA 21-1 [NN] groups); (2) declined to normal-level groups (CEA [HN] and CYFRA 21-1 [HN] groups); and (3) continuously high-level groups (CEA [HH] and CYFRA 21-1 [HH] groups). Survival analysis was conducted using the Kaplan-Meier method for each group. The Chi-square or Fisher exact test was employed to compare clinical and pathologic factors at the level of P < 0.05. The prognostic factor was evaluated by the Cox proportional hazards model. RESULTS: Compared with the continuously normal-level groups, the CEA [HN] group was significantly correlated to tumor size (P = 0.011), and the CYFRA 21-1 [HN] group was significantly correlated to tumor type and pathological TNM in addition to tumor size. Five-year survivals were significantly lower (P = 0.004) in the CEA [HH] group (67.3%) and the CEA [HN] group (86.5%) than in the CEA [NN] group (85.7%) and were significantly lower (P < 0.001) in the CYFRA 21-1 [HH] group (47.2%) and the CYFRA 21-1 [HN] group (70.1%) than in the CYFRA 21-1 [NN] group (90.1%). Multivariate analysis demonstrated that tumor size (21-50 mm), CEA [HH], and CYFRA 21-1 [HH] were independent unfavorable prognostic factors for overall survival (OS), whereas tumor size (21-50 mm), CEA [HH], CYFRA 21-1 [HN], and CYFRA 21-1 [HH] were independent significant prognostic factors for progression-free survival (PFS). CONCLUSION: Patients with a persistently high serum CEA or CYFRA 21-1 before and after surgery had shortest OS and PFS. These patients had worst prognosis. Adjuvant chemotherapy was likely to improve survival for these patients.