The aim of this study was to determine whether apolipoprotein A-I (ApoA-I) kinetics predict the overall survival in patients with advanced-stage non-small cell lung cancer (NSCLC) during platinum-based first-line therapy. A total of 125 NSCLC patients from January 2008 to September 2014 were retrospectively reviewed. Serum ApoA-I level was measured at baseline and thereafter at the start of each palliative chemotherapy cycle for all patients. Patients were divided into four groups according to ApoA-I kinetics. Patients whose ApoA-I ≥ 1.01 g/L and never decreased during treatment, patients whose ApoA-I ≥ 1.01 g/L and decreased (ApoA-I < 1.01 g/L) at least one time during treatment, patients whose ApoA-I < 1.01 g/L and normalized (ApoA-I ≥ 1.01) at least one time during treatment, and patients whose ApoA-I < 1.01 g/L and never normalized during treatment were assigned to non-decreased, decreased, normalized, and non-normalized ApoA-I groups, respectively. Overall survival rates were significantly different between the four groups, with 2-year survival rates of 88.6 and 17.5 % for the non-decreased and the decreased ApoA-I groups, respectively, and none survived 2 years later in the normalized and the non-normalized ApoA-I groups. When compared with the non-decreased group, the hazard ratios of death were 0.05, 0.44, and 1.73 in the normalized, decreased, and non-normalized groups, respectively (P < 0.001). Normalization of ApoA-I was associated with a low risk of progression, whereas patients with a decreased level of ApoA-I showed a progression of disease in most cases. ApoA-I can be a novel, widely available biomarker for patients with NSCLC.