Jonas F Ludvigsson,1– 3 Jiangwei Sun,1,4 Ola Olén,5– 7 Mingyang Song,8– 10 Jonas Halfvarson,11 Bjorn Roelstraete,1 Hamed Khalili,9,10,12 Fang Fang4 1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 2Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; 3Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, NY, USA; 4Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 5Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; 6Sachs’ Children and Youth Hospital, Stockholm South General Hospital, Stockholm, Sweden; 7Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; 8Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 9Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 10Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 11Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 12Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USACorrespondence: Jonas F Ludvigsson, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 171 77, Sweden, Email jonasludvigsson@yahoo.comBackground: Normal gastrointestinal (GI) mucosa on endoscopy has been linked to a lower risk of colorectal cancer (CRC) but its association to overall death is unknown.Methods: We identified 466,987 individuals with a first GI biopsy 1965– 2016 with normal mucosa (60.6% upper GI and 39.4% lower GI) through all Swedish pathology departments (n = 28). They were individually matched to 2,321,217 reference individuals without a GI biopsy and also compared to 505,076 full siblings. Flexible parametric models were applied to estimate hazard ratio (HRs) and 95% confidence interval (95% CI) for death.Results: During a median follow-up of ∼ 11 years, 85,859 (18.39%) of individuals with normal mucosa and 377,653 (16.27%) of reference individuals died. This corresponded to incidence rates of 147.56/10,000 vs 127.90/10,000 person-years respectively (rate difference: 19.66/10,000 person-years), with the multivariable-adjusted HR of 1.21 (95% CI: 1.20– 1.22). Excess mortality was seen for both upper and lower biopsy with normal mucosa. Particularly higher HRs for death were seen in males, individuals biopsied when aged < 40 years, those without a prior record of GI disease, and those with high education. Mortality risk was most increased in the first five years after biopsy (HR = 1.34; 95% CI: 1.32– 1.36) but decreased thereafter. Having a GI biopsy with normal mucosa was associated with excess mortality from cardiovascular (CVD)disease (HR = 1.02; 95% CI: 1.01– 1.03), cancer (HR = 1.58; 95% CI: 1.56– 1.61), GI disease (HR = 1.65; 95% CI: 1.58– 1.71), and other causes (HR = 1.10; 95% CI: 1.08– 1.11). Sibling comparisons yielded similar results.Conclusion: Compared with individuals without a GI biopsy, those with a normal GI biopsy due to clinical symptoms had a higher mortality particularly in the first five years after biopsy, and especially from GI disease and cancer.Keywords: normal mucosa, screening, mortality, cohort