The aim of the study was to describe in detail the impact of aging and comorbidities on safety and efficacy of gemcitabine-cisplatin in the subset of elderly with advanced NSCLC. We report the results of our study which enrolled patients aged over 65 years or older. This study included 46 patients consecutively admitted to our Department. Treatment consisted of gemcitabine 1250 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 2, of a 21-day cycle. The Charlson score method was chosen to evaluate the conditions of comorbidity. All patients were evaluable for toxicity and 44 for activity. A total of 128 courses were administered, with a median of 3 courses per patient and a dose-intensity of 93% and 88% for gemcitabine and cisplatin, respectively. Grade 3-4 neutropenia (22% of patients) and grade 3 asthenia (4.5%), emesis (4.5%) and nephrotoxicity (4.5%) were the most severe adverse events. Univariate analysis of toxicity did not show any significant difference among all groups. The overall response rate was 45.6% (95% CI, 31.3-60). At a median follow up of 13 months, the median and progression-free survival were 15 and 8 months, respectively. The multivariate analysis resulted in objective response and disease control being predictive of longer survival. The combination of gemcitabine and cisplatin appears to be an effective and tolerated regimen for elderly patients with advanced NSCLC, regardless of aging and condition of comorbidities. Prospective randomized trials based on specific geriatric assessment are required to obtain compelling information for the optimal management of elderly patients with advanced NSCLC.