Abstract Purpose: TNM Stage 3B encompasses a wide range of primary tumor and nodal metastatic tumor burden. This study aimed to evaluate the prognostic value of quantitative FDG PET/CT parameters in patients with newly diagnosed Stage 3B Non-Small Cell Lung Cancer (NSCLC). Materials and Methods: Institutional review board approved retrospective study identified patients diagnosed with Stage 3B NSCLC (8th edition TNM classification) on baseline FDG PET/CT at two medical centers (Medical centers A and B), between Feb 2004 and Dec 2014. Patients were excluded if they had prior NSCLC treatment or recent diagnosis of a second primary cancer. Quantitative FDG PET/CT parameters including whole body metabolic tumor volume (MTVwb), total lesion glycolysis (TLGwb), and maximum standardized uptake value (SUVmaxwb) were measured from baseline PET/CT using Edge method with Mimvista software. The primary endpoint was overall survival (OS). Cox proportional hazard regression and KaplanMeier overall survival analyses were used to test for an association between OS and quantitative FDG PET/CT parameters. The distributions of MTVwb, TLGwb, SUVmaxwb were skewed, so a natural logarithm transformation was applied and the transformed variables [(ln(MTVwb), ln(TLGwb), and ln(SUVmaxwb)] were used in the analysis. Results: The training set included 110 patients from center A with Stage 3B NSCLC. 78.2% of patients expired during follow-up. Median OS was 14 months. 1-year, 2-year, and 5-year OS was 56.5%, 34.6% and 13.9%, respectively. Univariate Cox regression analysis showed no significant difference in OS on the basis of age, gender, histology, ln(TLGwb), or ln(SUVmaxwb). ln(MTVwb) was positively associated with OS [hazard ratio (HR) of 1.23, p = 0.037]. This association persisted on multivariate Cox regression analysis (HR 1.28, p = 0.043), with adjustments for age, gender, treatment and tumor histology. External validation with 44 patients from center B confirmed increasing MTVwb was associated significantly worse OS. An MTVwb cut-off point of 85.6 mL significantly stratified Stage 3B NSCLC patient prognosis. Conclusion: MTVwb is a prognostic marker for OS in patients with Stage 3B NSCLC, independent of age, gender, treatment, and tumor histology. Keywords: Lung cancer, Tumor volume, FDG, PET/CT