Background: Pain is an independent prognostic factor for overall survival (OS) in non-small cell lung cancer (NSCLC). In in vitro and pre-clinical experiments, opioids promote angiogenesis and accelerate tumor growth and metastases. Opioid receptors are expressed in human NSCLC. Morphine stimulates proliferation and invasiveness of NSCLC cell lines by cross-activation of EGFR and other signaling pathways. Methods: To examine if long-term opioid requirement, independently of chronic pain, is associated with survival, we analyzed 209 patients diagnosed with stage IIIB/IV NSCLC at the Minneapolis VA and treated with chemotherapy. Pain was stratified by the proportion of time a patient reported severe pain (level 7-10 on a scale of 0-10; high pain (HP): 10% of the time, low pain (LP): <10% time). Opioids were converted to oral morphine equivalents (OME) (high opioid (HO): 5mg OME/day, low opioid (LO): <5mg OME/day). To separate pain levels from opioid exposure for analysis, four subgroups were created based on pain and opioid levels: LPLO, LPHO, HPLO and HPHO. The effects of pain, opioid requirement, and known prognostic variables on outcomes were analyzed in univariable and multivariable models. Results: Severe pain prior to chemotherapy initiation was associated with shorter OS (HR 1.39, 95% CI 1.02 - 1.87, p=0.035). Both high pain levels and high opioid requirement in the first 90 days after starting chemotherapy were strongly associated with shorter OS on univariable analysis. Remarkably, patients in the LPLO group during the first 90 days after starting chemotherapy had nearly 12 months longer median survival compared to the other 3 groups (17.9 months vs. 5.7 months (HPLO), 6.5 months (LPHO), and 6.2 months (HPHO), log-rank p=0.002). In multivariable models, longer survival in the LPLO group was sustained after adjustment for age, stage and performance status. Conclusions: Though usually related to each other, both higher chronic cancer-related pain levels and greater long-term opioid requirement are independently associated with shorter survival in advanced NSCLC. Prospective investigation of pain and opioid requirement is warranted to determine if opioid-sparing approaches improve outcomes.