OBJECTIVE Gastric cancer diagnosed from routine gastric biopsies without any evidence of a visible lesion and negative repeated biopsies is an infrequent but serious clinical problem for which gastrectomy has usually been recommended, even if operative specimens do not show cancer either. We report on a series of 22 such patients undergoing long-term follow-up after attempted treatment with photodynamic therapy (PDT). METHODS 22 patients with invisible gastric cancer (IGC) who presented during a 10-year period (10 men, mean age 56 +/- 15 years) were prospectively included. Initial histopathological findings confirmed by second opinion included 10 well-differentiated adenocarcinomas and 12 signet ring cell carcinomas. After two negative state-of-the art endoscopic reassessments, a single session of PDT using 5-delta-aminolevulinic acid (ALA) was performed in the area from which the biopsy was taken, and patients were followed up regularly. RESULTS After a mean follow-up period of 56.2 +/- 27.6 months, three patients had died of causes unrelated to gastric cancer, four had developed mucosal cancer that was successfully treated endoscopically after 4 - 38 months, and the remaining 15 patients remained without evidence of recurrent gastric cancer, lymph-node involvement, or metastases during a follow-up period of 54 +/- 26 months. CONCLUSIONS Our results suggest that gastrectomy may not be the only option for IGC, which might follow an uneventful natural course provided careful follow-up is scheduled. The role of PDT in this setting remains unclear and should be studied further.