The aim of this retrospective study was to evaluate the prognostic role of gross tumor volume (GTV) on survival of locally advanced NSCLC patients, regardless of TNM stage, and to analyze whether GTV and other radiotherapy (RT) parameters were important for the development of lung toxicity. Thirty-two patients with locally advanced NSCLC (stage IIIA bulky/IIIB) treated with chemoradiotherapy were retrospectively analyzed. Patients received induction chemotherapy followed by combination treatment (27 patients) or induction chemotherapy followed by RT alone (5 patients). Thoracic RT consisted in 60 Gy, with standard fractionation and was the same for all 32 patients. Dose volume histograms were collected from the 3D treatment plans and GTV, planning target volume, mean lung dose, volume of lung receiving more than 20 Gy or more than 30 Gy were analyzed. Survival was significantly longer in patients with a GTV < 100 cm(3) compared with patients having GTV > 100 cm(3) (p = 0.03). In a multivariate analysis only N-status and GTV were predictors of survival with a risk ratio of 0.51 and 0.62, respectively. Ten patients (31%) developed radiation pneumonitis grade 2 or higher. None of the RT parameters examined correlated significantly with the development of lung toxicity. In locally advanced NSCLC, GTV and N-status play a prognostic role even in patients at the same clinical stage and receiving a combination of chemo- and radiotherapy. This could imply a reassessment of the current staging system in patients with non-resectable NSCLC to better identify those patients who would benefit more from the combined treatment, despite its higher toxicity.