BACKGROUND: Barrett's esophagus (BE) with high-grade dysplasia (HGD) is a risk factor for development of esophageal carcinoma. Photodynamic therapy (PDT) with Photofrin (PHO) has been used to eliminate HGD in BE. OBJECTIVE: Our purpose was to compare PHOPDT plus omeprazole with omeprazole only (OM). DESIGN: Five-year follow-up of a randomized, multicenter, multinational, pathology-blinded HGD trial. SETTING: 30 sites in 4 countries. PATIENTS: 208. INTERVENTIONS: Patients with BE and HGD were randomized (2:1) to PHOPDT (n=138) or OM (n=70) into a 2-year trial followed up for 3 more years. PHOPDT patients received 2 mg/kg PHO intravenously followed by endoscopic laser light exposure of Barrett's mucosa at a wavelength of 630 nm within 40 to 50 hours to a maximum of 3 courses at least 90 days apart. Both groups received 20 mg of OM twice daily. Pathologists at one center assessed biopsy specimens in a blinded fashion. MAIN OUTCOME MEASUREMENT: HGD ablation status over 5 years of follow-up. RESULTS: At 5 years PHOPDT was significantly more effective than OM in eliminating HGD (77% [106/138] vs 39% [27/70], P<.0001). A secondary outcome measure preventing progression to cancer showed a significant difference (P=.027) with about half the likelihood of cancer occurring in PHOPDT (21/138 [15%]) compared with OM (20/70 [29%]), with a significantly (P=.004) longer time to progression to cancer favoring PHOPDT. LIMITATIONS: Not all patients were available for follow-up. CONCLUSIONS: This 5-year randomized trial of BE patients with HGD demonstrates that PHOPDT is a clinically and statistically effective therapy in producing long-term ablation of HGD and reducing the potential impact of cancer compared with OM.