AIM: To detect human papillomavirus (HPV) in the esophageal mucosa and the possible relationship with esophageal cancer in Greece.METHODS: Forty-nine patients underwent esophagogastroduodenoscopy (EGD) and esophageal biopsy at a university hospital that acts as a referral center for Northern Greece. Nineteen of these patients (14 male and 5 female) had esophageal squamous cell carcinoma (ESCC) and 30 (15 male and 15 female) did not have any reported esophageal malignancy. Histopathological assessment was followed by polymerase chain reaction analysis of all the samples. Patient demographic data (age, sex, and place of birth) and information regarding smoking habits, alcohol consumption or sexual habits were collected. A method of statistical interference, verification of hypotheses based on homogeneity and independent χ(2) test, was used.RESULTS: From the 49 patients that underwent EGD and biopsy, 19 had ESCC and 30 had normal esophageal mucosa, with a mean age of 65.2 years. Regarding the prevalence of oncogenic risk factors for esophageal carcinoma, an interesting conclusion was that 78% of the patients used tobacco and almost one-third had multiple sexual partners, whereas only 20% of the patients consumed alcohol, which was not statistically significant, when compared to the control group. In the ESCC group, the only two positive samples were among the male patients (2/14 male patients with ESCC, 14.5%). No HPV was identified in the control group. The predominant HPV types identified were 11 and 31, which have a low malignancy potential. The presence of HPV DNA in the ESCC group was not statistically significant, 95% confidence interval (χ2=3.292, P=0.07).CONCLUSION: This is the first relevant study in Greece, and despite the lack of statistical significance, the issue of HPV infection and ESCC does merit further investigation.