Recently targeted therapy and immunotherapy have been demonstrated to improve survival in non-operable, non-small cell lung cancer (NSCLC) patients. The results of salvage lung resection in patients with initially unresectable advanced NSCLC after immune checkpoint inhibitor (ICI) or Target Therapy (TT) treatment remain limited and unclear. We aimed to define the outcomes of patients undergoing salvage surgery in a real-life setting. A case series study evaluation of clinical data from patients submitted to salvage surgery was performed. Patients included in the study were judged inoperable, according to a multidisciplinary tumor board decision, before being submitted to ICI or TKI treatment. Data were analyzed using Chi-squared, Fisher's and Wilcoxon rank-sum tests, where appropriate. Eighteen patients were enrolled. Sixty-seven per cent were Stage IIIB and IV. Fifty per cent of cases received TKI treatment, the remaining patients received ICI alone or with chemo- and/or radiotherapy. Twenty-two per cent of cases were scheduled and successfully performed by minimal invasive approach without needing for conversion. Overall, 5 patients (28%) developed postoperative complications, the 90-day mortality was zero. The major pathologic response rate was 27.7%. The median OS was months 24.7 months with sixteen of 18 patients alive (89%) at last follow-up. No difference was recorded between TT and ICI group in term of complication rate, length of hospital stay and survival. In our experience, salvage surgery after ICI or TT have reasonable post-operative and long-term outcomes. Salvage surgery could be proposed in selected patients after a careful multidisciplinary evaluation.