Background: Activating mutations of the epidermal growth factor receptor (EGFR) were discovered over 10 years ago. EGFR mutations predict increased response rates and progression-free survival (PFS) when treated with EGFR tyrosine kinase inhibitors (TKIs) compared to combination chemotherapy in advanced NSCLC. However, long-term outcomes including 5-year survival among patients (pts) with EGFR-mutant metastatic NSCLC treated with EGFR-TKIs remain heterogeneous. Herein, we define clinical factors associated with prolonged overall survival (OS) in this cohort. Methods: A retrospective analysis was performed of pts with metastatic NSCLC harboring a sensitizing EGFR mutation and treated with EGFR-TKIs at Dana-Farber Cancer Institute between Jan 1, 2002 and Sept 31, 2009. Pts alive at time of analysis must have had at least a 5-year survival. OS was compared based on clinical features using log-rank test. Cox’s proportional hazards models were used to estimate hazard ratios. Results: Among 134 pts, median PFS and OS were 13.1 mos (95% CI, 10.8-14.6) and 30.9 mos (95% CI, 28.2-35.7), respectively. 19 pts (14.2%) were long-term survivors (OS ≥ 5 years), of whom 10 remained alive at the time of analysis with median follow-up of 89.8 mos (range, 60.1-91.6). Multivariate analysis adjusted for factors significant at the 0.10 level in univariate models revealed that sensitizing EGFR mutations in exons other than exon 19 (n = 55) (HR 1.53; 95% CI, 1.05-2.23; p = 0.03), extrathoracic mets (n = 77) (HR 1.58; 95% CI, 1.04-2.43; p = 0.03) or brain mets (n = 29) (HR 2.17; 95% CI, 1.34-3.51, p = 0.002) at the time of diagnosis, and current smoking status (n = 5) (HR 4.31; 95% CI, 1.64-11.32; p = 0.003) were independent predictors of shorter OS. Age, gender, disease stage at diagnosis, liver or adrenal mets at diagnosis, specific TKI (erlotinib vs gefitinib), or line of TKI treatment did not correlate with OS. Conclusions: Our data estimate 5-year OS among EGFR-mutant metastatic NSCLC pts treated with EGFR-TKIs at 14%--vs less than 5% in historic results for an unselected population with distant-stage NSCLC. Planned studies will elucidate the genetic alterations that may co-occur with EGFR mutations and influence treatment outcomes.