The purpose of this study is to investigate the impact of positive cancer/lung cancer family history (FH) on clinical features and outcome in non-small cell lung cancer (NSCLC) patients. We analyzed 4,491 NSCLC patients with NSCLC who presented from January 1999–December 2005. Chi-square test and Wilcoxon test were used for univariate comparisons, while Cox Proportional Hazards regression analysis was performed to evaluate the adjusted risk of death. Univariate probability of survival was calculated using Kaplan-Meier estimate and compared using the log-rank test. Of 4,491 patients, 579 patients (12.89%) had positive FH, including 233 patients (5.19%) with FH of lung cancer. Patients with positive lung cancer FH, compared to those with negative FH, were diagnosed at earlier age (57 vs. 60; P < 0.001), presented more cases of adenocarcinoma (58.80 vs. 50.69%; P = 0.016), and at more advanced stage (Stage IIIB/IV 45.74 vs. 36.79%; P < 0.001). These differences were also detected in patients with positive cancer FH. In addition, more females and non-smokers were among patients with positive cancer FH (30.05 vs. 26.15%; P = 0.045 and 39.90 vs. 33.82%; P = 0.008, respectively). Furthermore, patients with advanced cancer (stage IIIB/IV) who had positive FH had lower response rate to chemotherapy (CR&PR 24.68 vs. 34.42%; P = 0.024). Nevertheless, patients with positive lung cancer FH had better prognosis (P = 0.015), especially if diagnosed at an early stage (P = 0.035), and their adjusted relative risk of death was lower (RR 0.69; 95% CI: 0.51–0.93; P = 0.015). Definite epidemiologic and survival differences exist between NSCLC patients with positive or negative FH of cancer. Our results suggest that cancer FH is an important factor of clinical features, and could serve as a prognostic indicator for NSCLC.