Purpose: This systematic analysis was conducted to evaluate the efficacy and safety of pemetrexed-based chemoradiotherapy in treating patients with locally advanced or metastatic esophageal cancer. Methods: Clinical studies evaluating the efficacy and safety of pemetrexed based regimens on response and safety for relevant patients were identified using a predefined search strategy. Pooled response rates (RRs) were calculated. Results: For pemetrexed-based regimens, 4 clinical studies including 47 patients with locally advanced or metastatic esophageal cancer were considered eligible for inclusion. Systematic analysis showed that, in all patients, the pooled RR was 51% (24/47). Major adverse effects of grade III/IV were esophagitis, neutropenia, thrombocytopenia, anemia anorexia, fatigue, diarrhea, dysphagia and vomiting. No treatment related death occurred with pemetrexed-based treatment. Conclusion: This systematic analysis suggests that pemetrexed based radiotherapy is associated with reasonable activity and good tolerability in treating patients with locally advanced or metastatic esophageal cancer.