The objective of this study was to determine if a combination of recombinant adenovirus 2 p53 (rAd2p53) gene therapy and radiotherapy would have significantly improved outcome from esophageal carcinoma when compared to radiotherapy (RT) alone. Forty-five patients diagnosed with esophageal carcinoma (confirmed squamous cell carcinoma) were randomly assigned to one of two study arms: treatment group: rAd2p53 gene therapy + RT (n = 22); and control group: radiotherapy (n = 23). For the treatment group, rAd2p53 was injected into multiple areas of the lesion once a week for 6 weeks avoiding deep ulcers points. RT was administered after 3 days of injection of rAd2p53. Patients in the control group only received radiotherapy. The overall response rate was significantly higher in the treatment group than in control group (P < 0.05). Furthermore, the complete response rate was 3 times higher in the treatment group than in the control group (P < 0.05). Transient fever and pain at injection site were the only side effects mentioned in the treatment group. In conclusion, this recombinant virus-RT combination is significantly more beneficial in palliation than RT alone, with minor side affects. However, its role as neoadjuvant therapy prior to surgical resection needs to be further investigated.