Abstract Background We conducted a trial of a new less invasive, locoregional modality for lung cancer with pleural spread. This study was planned to investigate the feasibility, safety, and pharmacokinetics of pleural perfusion thermochemotherapy (PPTC) under video-assisted thoracoscopic surgery (VATS) and its modified method with a short perfusion time for preventing heat damage to the lung during the procedure. Methods Seventeen patients, 59 to 79 years old, underwent surgical resection of the primary lesions and PPTC under VATS without thoracotomy. All had pleural spread with malignant effusion due to lung cancer proven before the treatment. PPTC consists of irrigating the pleural space with 42°C saline solution containing cisplatin (200 mg/m 2) using a devised circuit. The time for perfusion was two hours in 10 patients (group L), and one hour in 7 patients (group S). Results All patients successfully completed this treatment with acceptable toxicities. The pharmacokinetic analysis showed that high platinum levels for the regional pleural exposure, which was 20- to 40-fold greater than those for the plasma in both groups. These values were equivalent between the groups, although the levels for the plasma were higher in group L than in group S. Postoperative lung damage was seen in 4 patients with no serious conditions in group L, and none in group S. The median survival for the L and S groups was 17 and 19 months, respectively. Conclusions This less invasive modality seems to offer a safe, feasible, and pharmacokinetically advantageous procedure to have excellent local control for lung cancer with pleural spread.