Background: Advanced stage non-small cell lung cancer (NSCLC) is a heterogenous disease, yet, with the exception of targeted therapies, most guidelines recommended uniform treatment irrespective of tumor burden or sites of metastases and this may explain, in part, the wide range of responses to same lines of therapy. Aim of work: In this work we tried to explore the effect of metastatic sites in on overall survival (OS), in an unselected group of Non-small cell lung cancer patients who received different treatments line. Methods: A retrospective analysis was performed on patients with stage IV NSCLC who received systemic treatment at UAB Cancer Center (NCI designated comprehensive cancer center) between 2002 to 2012. The details of sites of metastases, systemic therapy and overall survival were recorded for each patient. Result: In 409 patients who received systemic treatment, there was statistically significant lower OS in those presenting with liver metastases (p < 0.001), adrenal metastases (p=0.011) and metastases to abdominal lymph nodes (p=0.014). There was no statistically significance difference in OS in patient presenting with pleural metastases or effusion (p=0.908), metastases to heart or pericardium (p=0.654), metastases to bone (p=0.281), brain (p=0.717) or skin and subcutaneous tissue (p=0.642). Conclusion: Intra-abdominal metastases confer a particularly poor prognosis in stage IV NSCLC treated with systemic therapy and may identify patients in whom aggressive treatment beyond first line therapy is not appropriate.