This retrospective study was conducted to determine whether endostatin improves the efficacy and safety of platinum-based chemotherapy administered via both intravenous and arterial infusions for stage III/IV non-small-cell lung cancer (NSCLC). Seventy one patients with confirmed pathological or cytological diagnosis of NSCLC from January 2008 to March 2013 were enrolled for the study. Patients received three different therapeutic regimens until disease progression or an intolerable toxicity was evidenced. Group C received chemotherapy administered by intravenous injection and subsequent radiotherapy. Group IC received chemotherapy by intravenous injection and arterial infusion plus radiotherapy. Group IC + E patients were treated with chemotherapy plus Endostatin injected arterially and intravenously and subsequent radiotherapy. Group IC + E showed a progression-free survival (PFS) of 12 months as compared to 7 months of group C, a significant increase indeed (p = 0.037). Likewise, the overall survival time higher in Group IC + E and Group IC was compared to Group C (p = 0.001; p = 0.004, respectively). The adverse or toxic side effects exhibited by Group IC + E were not significantly different from either Group IC or Group C. Endostatin administered in combination with chemotherapeutic agents via both intravenous injection and arterial infusion enhanced the PFS and OS in advanced NSCLC without increasing the risk of toxicity.