Background: Acute chemotherapy-associated exacerbation of interstitial lung disease (ILD) can occur in patients with non-small cell lung cancer (NSCLC). The safety and efficacy of cytotoxic chemotherapy has not yet been established for NSCLC with ILD. Thus, patients with advanced NSCLC with ILD usually receive only best supportive care. The aim of this study was to assess the safety and efficacy profiles of the combination chemotherapy of vinorelbine and a platinum agent in patients with advanced NSCLC with ILD. Patients and Methods: Nineteen patients with advanced NSCLC with ILD treated with vinorelbine and a platinum agent, either cisplatin or carboplatin, were retrospectively reviewed to examine acute exacerbation of ILD, toxicity, response rate, and survival time. Additionally, possible predictive factors for acute chemotherapy-associated exacerbation of ILD were analyzed. Results: The response rate was 42.1%, the progression-free survival time was 4.4 months, the median survival time was 7.4 months, and the one-year survival rate was 36.8%. Neutropenia was the most frequent grade 3 to 4 toxicity and it occurred in 63.2% of patients. Acute chemotherapy-associated exacerbation of ILD occurred in three patients (15.8%) and caused the death of one of these patients (5.3%). No variables were identified as being predictive factors for acute chemotherapy-associated exacerbation of ILD. Conclusion: The combination chemotherapy with vinorelbine and a platinum agent can be considered as a treatment option for patients with advanced NSCLC with ILD, with careful management after sufficient evaluation of the risks and the benefits.