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The primary aim of this prospective, multicentric study was to assess the intestinal activity and health-related quality-of-life (HRQL) after ileocecal valve removal. The secondary aim was to evaluate any vitamin B12 deficiency. The study included patients undergoing right colectomy, extended right colectomy and ileocecal resection for either neoplastic or benign disease. Selected items of GIQLI and EORTC QLQ-CR29 questionnaires were used to investigate intestinal activity and HRQL before and after surgery. Blood samples for vitamin B12 level were collected before and during the follow-up period. The empirical rule effect size (ERES) method was used to explain the clinical effect of statistical results. Linear mixed effect (LME) model for longitudinal data was applied to detect the most important parameters affecting the total score. A total of 158 patients were considered. Applying the ERES method, the analysis of both questionnaires showed clinically and statistically significant improvement of HRQL at the end of the follow-up period. Applying the LME model, worsening of HRQL was correlated with female gender and ileum length when using GIQLI questionnaire, and with female gender, open approach, and advanced cancer stage when using the EORTC QLQ-CR29 questionnaire. No significant deficiency in vitamin B12 levels was observed regardless of the length of surgical specimen. In our series, no deterioration of HRQL and no vitamin B12 deficiency were found during the follow-up period. Nevertheless, warning patients about potential changes in bowel habits is mandatory. In our series, no deterioration of HRQL and no vitamin B12 deficiency were found during the follow-up period. 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