The efficacy of S-1 monotherapy as a 2nd-line regimen for elderly patients with non-small cell lung cancer (NSCLC) has not been reported, nor has delayed onset regression after temporary progression of tumor during an identified therapeutic regimen. Here we report a 78-year-old man was diagnosed with T3N3M1b (BRA), stage IV squamous cell lung cancer. His primary lesion progressed after whole brain irradiation and 4 cycles of 1st-line chemotherapy with docetaxel. S-1 monotherapy was prescribed as the 2nd-line treatment. Each cycle of chemotherapy comprised 14 days of S-1 (40 mg, twice daily) followed by 14 drug-free days. After 6 months of S-1 monotherapy, primary and metastatic lesions had started regressing significantly. He continued S-1 monotherapy for 19 months (20 cycles) with a comfortable daily life until reaching progressive disease. S-1 monotherapy as a 2nd-line could be a therapeutic option for elderly patients with NSCLC. Moreover, long-term use of S-1 might be worth trying if adverse events and tumor growth are tolerable and other anti-cancer drugs are not applicable, because S-1 has a potential for delayed onset efficacy.