Abstract. Treatment with 5-fluorouracil (5-FU) and cisplatin (PF regimen) remains the most frequently used chemotherapy for esophageal squamous cell carcinoma (SCC). The aim of the present study was to assess the efficacy and safety of pemetrexed/cisplatin (PP regimen) as definitive treatment compared with PF. A total of 60 patients with locally advanced, unresectable SCC of the esophagus receiving concomitant chemoradiotherapy were recruited in this study; of those patients, 29 received four cycles (two concomitant and two post-radiotherapy) of the PF regimen (arm A, cisplatin 25 mg/m 2 /day i.v. on days 1-3 plus 5-FU 800 mg/m 2 /24 h by continuous infusion on days 1-5) and 31 received four cycles of the PP regimen (arm B, cisplatin 25 mg/m 2 /day i.v. on days 1-3 plus pemetrexed 500 mg/m 2 on day 1). All the patients in both arms received a total radiation dose of 59.6 Gy. The two arms were well-matched for age, gender, Karnofsky performance status, TNM stage, tumor location and length. The overall response rate was 89.7% in arm A vs. 93.5% in arm B (P>0.05). The median overall survival was 26.1 months [95% confidence interval (CI): 15.3-36.8 months] in arm A vs. 28.7 months (95% CI: 9.4-48.0 months) in arm B (P>0.05). Severe esophagitis occurred in 31.0% (9/29) of the patients in arm A vs. 12.9% (4/31) of the patients in arm B; the difference was statistically significant (P= 0.036). Grade 3/4 leukopenia and thrombocytopenia occurred in 4 (13.8%) and 1 (3.4%) patients, respectively, in arm A vs. 12 (38.7%) and 6 (19.4%) patients, respectively, in arm B; the differences were statistically significant (P=0.029 and 0.041, respectively). Therefore, chemoradiotherapy with the PP regimen achieved therapeutic results comparable with those of the PF regimen; in terms of toxicity, the incidence of hematological toxicity was higher and that of esophagitis was lower with the PP regimen.