It is controversial whether a tumor located in the lower lobe is related with worse outcome of non-small cell lung cancer (NSCLC). This study aimed to clarify the prognostic role of primary tumor location in NSCLC. Patients newly diagnosed with NSCLC in a tertiary referral hospital from January 2011 to December 2014 were followed up for 5 years. Of the 2,289 NSCLC cases, 911 (39.8%) cases pertained to lower lobe cancers. Patients with lower lobe cancer showed a higher all-cause mortality rate than those with non-lower lobe cancer (48.6% vs. 40.3%, p < 0.001). Patients with lower lobe cancer had a lower proportion of adenocarcinoma histology and epidermal growth factor receptor (EGFR) mutations. Furthermore, compared to patients with non-lower lobe cancer, those with lower lobe cancer had a higher level of tumor markers (neuron-specific enolase and cytokeratin fragment 21-1). Mediation analysis revealed that the association between lower lobe cancer and higher all-cause mortality could be explained by an indirect pathway through EGFR mutations (percent mediated = 17.3%, p = 0.005). The sensitivity analysis for adenocarcinoma patients showed similar results (percent mediated = 18.8%, p = 0.021). Lower lobe cancer is associated with a higher all-cause mortality risk in patients with NSCLC, which is partly mediated by a lower proportion of EGFR mutations.