The aim of this study was to understand the clinicopathological and prognostic significance of promoter methylation of Fragile Histidine Triad (FHIT) gene in esophageal cancer. FHIT methylation in 257 primary esophageal squamous cell carcinomas was retrospectively analyzed by methylation-specific polymerase chain reaction. Aberrant methylation of FHIT was found in 85 (33%) of 257 esophageal cancer patients. The FHIT methylation was found to be significantly associated with exposure to tobacco smoke (P = 0.007) and with a poor prognosis in cases of stage 1-2 cancer irrespective of recurrence. The hazard of failure after esophagectomy for stage 1-2 cancers with FHIT methylation was about 5.81 (95% CI = 1.15-14.07; P = 0.009) times higher than in those without. Recurrence occurred in 116 (45%) of the 257 patients studied. The survival after recurrence in stage 1-2 cancers was also poorer for patients with FHIT methylation than in those without (HR = 2.31; 95% CI = 1.18-7.92; P = 0.03). In conclusion, aberrant methylation of the FHIT promoter was found to be significantly associated with exposure to tobacco smoke and with a poor prognosis for stage 1-2 cases, but not with recurrence rate. Our study suggests that FHIT promoter methylation may be an independent prognostic biomarker in early stage esophageal squamous cell carcinoma.