Background: There is a variety of chemotherapy regimens used as first-line treatment in advanced non-small cell lung cancer (NSCLC). Few studies have used real-world data to compare the clinical outcomes associated with different chemotherapy combinations. The study objective was to compare overall survival between chemotherapy regimens used for patients with advanced NSCLC in an integrated healthcare system. Methods: This retrospective cohort analysis included patients age 18 or older from Northern and Southern California Kaiser Permanente with a diagnosis of Stage IIIB/IV NSCLC identified in the cancer registry. First chemotherapy date occurred from January 2008 through September 2012 with at least 6 months of follow up to March 31, 2013. Overall survival was measured as the number of months from initial chemotherapy until death, end of enrollment or March 31, 2013. Chemotherapy regimens were categorized into five mutually exclusive groups: pemetrexed-based, pemetrexed + bevacizumab, bevacizumab-based, platinum doublets and singlets. Survival was compared between the five groups using Cox proportional hazard models, adjusting for age, gender, race, region, stage, histology, days from diagnosis to initial chemotherapy and Diagnostic Cost Group (DxCG) risk score. The analysis was performed for all age groups and by age over and under 65. Results: Among 1,989 adults, those that received singlet chemotherapy were at significantly increased risk of mortality compared to doublets (HR 1.23; 95% CI 1.02-1.49). Patients younger than 65 who had received pemetrexed + bevacizumab regimens were at significantly reduced risk of mortality (HR 0.58; 95% CI 0.35-0.95) when compared to platinum doublets. Among patients over 65, there were no significant differences in survival between the chemotherapy regimens. Conclusions: Adult patients with advanced NSCLC who are younger than 65 years old have improved survival after receiving pemetrexed + bevacizumab chemotherapy regimens compared to platinum doublet regimens. No survival differences were found between regimens in patients over the age of 65.