Esophageal squamous cell carcinoma (ESCC) demonstrates wide regional variation in incidence and causal associations. Human papillomavirus (HPV) has been implicated in ESCC, particularly the sub-types 16 and 18. Transforming proteins E6 and E7 from these high risk sub-types, interact with p53 protein and Rb protein respectively, leading to loss of function of these tumor suppressor gene products. These interactions further lead to inactivation of the growth suppressive effects of the p53 and Rb proteins, resulting in abnormal proliferative states. p53 protein expression has been found in both HPV-positive and -negative tumors, indicating that HPV and p53 protein expression are not mutually exclusive and can occur together in the same tumor. It has been observed that HPV plays a more significant role in esophageal carcinogenesis in geographic areas with a high prevalence of the disease. A variation in the association between HPV and ESCC worldwide may be due to environmental and geographic factors, or to genetic susceptibility to esophageal HPV infections. Variations in the sensitivity of techniques used in the detection of the virus and in the methodology for processing the tumor tissues, may also be responsible for global differences. Esophageal carcinogenesis is a complex multistep process with a multifactorial etiology. Infection with oncogenic HPV types may be an integral part in a multistep process that leads to ESCC.