The involvement of human papillomavirus (HPV) in the carcinogenesis of esophageal squamous carcinoma remains undetermined. However, three genome-wide association studies of esophageal cancer have identified a shared susceptibility locus at 10q23 (rs2274223: A5780G) in phospholipase C epsilon 1 (PLCE1). The current study aims to present a comprehensive and novel spectrum about the HPV genotype distribution of esophageal carcinoma in Kazakhs and assess its association with PLCE1 polymorphisms. The HPV genotypes in 183 patients with esophageal cancer and 89 controls selected from the Kazakh population were evaluated using the HPV gene chip. The PLCE1 rs2274223 variant was genotyped in esophageal carcinoma patients by MALDI-ToF Mass Spectrometry. The presence of seven HPV genotypes in esophageal carcinoma tissuesincluding HPV 16, 18, 35, 52, 6, 11, 43was significantly higher at 31.7% than those in controls at 9.0% (P<0.001). Such presence was strongly associated with increased risk of esophageal carcinoma (OR 4.70; 95% CI 2.13-10.36). Among all HPV genotypes detected, HPV16 was the most common genotype identified (29.0%, OR 4.13; 95% CI 1.87-9.13), which is significantly associated with well-differentiated esophageal carcinoma (P=0.037). HPV-positive patients were generally younger than HPV-negative patients (70.1% vs. 29.3%, P=0.013). PLCE1 rs2274223 genotypes AG and AG/GG were significantly associated with HPV-positive patients with esophageal carcinoma (OR 2.05, 95% CI 1.03-4.08 and OR 1.98, 95% CI 1.02-3.84, respectively). These findings suggest that heterozygote of PLCE1 rs2274223 increases susceptibility to HPV infection in patients with esophageal carcinoma among the Kazakh populations. J. Med. Virol. 86:608-617, 2014. (c) 2013 Wiley Periodicals, Inc.