Background: Patients with esophageal cancer often undergo 201Tl myocardial imaging for preoperative risk evaluation, thereby providing an excellent opportunity to assess tumor handling of 201Tl. We thus compared the characteristics of 201Tl and 18F-FDG uptake by esophageal cancer and further investigated their prognostic values. Methods: The study included 100 newly diagnosed esophageal cancer patients who underwent preoperative 201Tl SPECT and 18F-FDG PET exams. Tumor to mediastinal uptake (T/M) ratio and retention index (RI) of 201Tl, tumor 18F-FDG pSUV, tumor size, location, and stage were assessed. Survival analysis was performed for disease-free survival using the Kaplan-Meier method. Cox proportional hazard models were used to determine independent risk factors. Results: 201Tl SPECT and 18F-FDG PET visualized the primary tumor in 85/100 (85.0%) and 91/100 (91.0%) patients, respectively (p = 0.03). There were close correlations between early and delayed 201Tl T/M ratios (r = 0.83, p < 0.0001) and between T/M ratios and 18F-FDG pSUV (r = 0.56 and 0.57, respectively, both p < 0.0001). Both T/M ratios and 18F-FDG pSUV correlated significantly with tumor stage (ρ = 0.45, 0.40, and 0.59, respectively, all p < 0.0001). Survival analysis revealed tumor size, 201Tl negative tumors, 18F-FDG negative tumors, delayed 201Tl T/M ratio, RI, stage, and 18F-FDG pSUV to be significant univariate predictors for disease-free survival. Multivariate survival analysis showed stage (p = 0.02) to be a significant independent prognostic predictor. Conclusions: In patients with esophageal cancer, assessment of tumor 201Tl uptake, as with 18F-FDG, may provide potentially useful information regarding tumor characteristics.