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Periampullary region tumors (PRTs) are the fifth highest cause of cancer-related deaths worldwide. Although recent studies have highlighted the prognostic value of the long noncoding RNA HomeoboxA transcript at the distal tip (HOTTIP) in patients with pancreatic ductal adenocarcinoma, the relationship between HOTTIP and clinical outcome of all PRTs remains obscure. The aim of this study was to clarify the prognostic significance of HOTTIP in patients with all PRTs related to KRAS mutational status.HomeoboxA transcript at the distal tip expression was detected in 100 PRT samples using quantitative real-time polymerase chain reaction. The associations between HOTTIP levels, clinicopathological factors, and patient prognosis were also analyzed.The expression of HOTTIP was found to be significantly upregulated by 32-fold (P = 0.031) in tumor tissues compared with normal tissues. The over expression of HOTTIP was related with presence of invasion and metastasis (P = 0.0467, P = 0.0256). In addition, increased HOTTIP expression was associated with poor prognosis independent of KRAS mutation (P < 0.001; n = 72). Moreover, multivariate analysis showed that high HOTTIP expression was an unfavorable prognostic factor for overall survival.Our findings indicate that high levels of HOTTIP expression have the potential to be an independent, unfavorable prognostic factor for patients with PRT.