Photodynamic therapy (PDT) is an ablative treatment leading to intracellular photoexcitation and injury. A total of 15 patients with superficial esophageal squamous cell carcinoma (ESCC) without metastasis underwent PDT and 48-72 h after intravenous Photofrin, the patients were treated with a 630-nm excimer dye laser. A total of 13 patients had local tumor recurrence after definitive chemoradiotherapy (CRT) consisting of 5-fluorouracil (5-FU) and cisplatin (CDDP). Of 6 patients, 5 had submucosal ESCC and were treated with S-1. Complete reponse was achieved by 11 patients with initial PDT, but 2 had recurrences. The recurrent/residual tumors were successfully treated with repeated PDT. Two patients with intramucosal ESCC succumbed due to metastatic disease, but 11 patients were disease-free. The 5 patients treated with S-1 remained alive despite submucosal ESCC. PDT was applied to human ESCC cells in vitro in the presence or absence of 5-FU or CDDP. The combination of PDT with 5-FU or CDDP resulted in enhanced cytotoxic effects, thereby reducing the effective dosage of each drug. PDT is a promising treatment option for selected ESCC cases, particularly for local recurrence following CRT. Our experience suggests that PDT is more effective when combined with chemotherapy.