Background: Comorbidities reflect patients’ underlying multiple-disease growth curve and influence outcomes of treatment. However, it is unclear if there is and how much independent prognostic value of the Charlson Comorbidity Index (CCI) present among patients with non-small cell lung cancer (NSCLC). We aimed to evaluate the independent prognostic value of CCI using a large sample of NSCLC patients. Methods: From the database of our Cancer Center Cancer Registry, we found 2,510 patients with NSCLC who were diagnosed and treated at our institution from 2004 to 2014. The patients were enrolled based on the following inclusion criteria: 1) had undergone a baseline FDG PET/CT, 2) had no evidence of brain metastasis, and 3) did not have concurrent diagnosis or a history of other primary cancer. A total of 949 patients were enrolled for this retrospective study to identify 19 comorbidities defined by the Charlson, et al., for calculating CCI at the baseline. Overall survival (OS) was determined from the FDG PET date to the death from any cause. Other covariates included age, gender, and race, smoking history, and tumor histology, clinical TNM stage (7th edition) and treatment types. Survival analyses using Cox Proportional Hazard models were performed to determine the independent prognostic value of the CCI. Results: Among the 949 NSCLC patients, 429 (45%) were male, 452 (48%) black, with mean age 67 (s.d. 11), and median survival of 24 months. The number of patients with TNM stage IA, IB, IIA, IIB, IIIA, IIIB, and IV were 171 (18%), 103 (11%), 67 (7%), 40 (4%), 164 (17%), 107 (11%), and 297 (31%), respectively. 353 (37%) patients had no comorbidity at the baseline; 251 (26%) patients had a CCI of 1; 171 (18%) of patients had a CCI of 2; and 99 (10%) had a CCI of 3; and 75 (8%) patients had a CCI of 4 or higher. Controlling for TNM stage, age, gender, race, tumor histology, and treatment types, the adjusted hazard ratio of CCI on OS is 1.09 (95% CI 1.03, 1.15, p = 0.01). When CCI was modeled as a categorical variable, the effect size of CCI became increasingly larger as the value of CCI increased. Conclusions: CCI is a significant prognostic factor with increasing magnitude of effect on OS as the value of comorbidities increases.