BACKGROUND: Pain is associated with shorter survival in non-small cell lung cancer (NSCLC). Lung cancer cells express opioid receptors. Opioids promote angiogenesis, tumour growth, and metastases, and shorten survival in animal models. METHODS: We examined retrospectively if long-term opioid requirement, independently of chronic pain, is associated with reduced survival in 209 patients with stage IIIB/IV NSCLC. Opioid doses were converted to average oral morphine equivalents (OME). Patients were stratified by proportion of time they reported severe pain, and required <5 or >/=5 mg day(-1) OME. Effects of pain, opioid requirement, and known prognostic variables on overall survival were analysed. RESULTS: Severe pain before chemotherapy initiation was associated with shorter survival (hazards ratio 1.39, 95% confidence interval, 1.02-1.87, P=0.035). The magnitude of pain and opioid requirement during first 90 days of chemotherapy were predictive of shorter survival: patients with no/mild pain and requiring <5 mg day(-1) OME had 12 months longer median survival compared with those requiring more opioids, experiencing more pain, or both (18 compared with 4.2-7.7 months, P=0.002). Survival differences (16 compared with 5.5-7.8 months, P<0.001) were similar when chronic pain and opioid requirement were assessed until death or last follow-up. In multivariable models, opioid requirement and chronic pain remained independent predictors of survival, after adjustment for age, stage, and performance status. CONCLUSIONS: The severity of chronic cancer-related pain or greater opioid requirement is associated with shorter survival in advanced NSCLC, independently of known prognostic factors. While pain adversely influences prognosis, controlling it with opioids does not improve survival. Prospective studies should determine if pain control using equi-analgesic opioid-sparing approaches can improve outcomes.