Objective Development of novel treatments for coeliac disease (CeD) is dependent on precise tools to monitor changes in gluten-induced mucosal damage. Current histology measures are subjective and difficult to standardise. Biopsy proteome scoring is an objective alternative to histology which is based on robust changes in biological pathways that directly reflect gluten-induced mucosal damage. In this study we aimed to evaluate biopsy proteome scoring as effect measure in a clinical trial setting by measuring intestinal remodeling in response to oral gluten challenge. Design We analyzed biopsies from a gluten challenge trial of treated CeD patients that consumed 3 g (n=6) or 10 g (n=7) gluten per day for 14 days. Sections from individually embedded biopsies collected before and after challenge were processed for proteome scoring (n = 109) and measurement of Vh:Cd ratio (n = 58). Proteome scores were compared to histology, intraepithelial lymphocyte (IEL) frequency and plasma interleukin-2 (IL-2). Results Change in proteome scores were significant for the group of patients who consumed 10 g gluten, but not for the group who consumed 3 g gluten. Altogether, 8 of 13 patients had changes in delta proteome scores above cut-off. Proteome scores correlated with Vh:Cd ratios both at run-in and at day 15. Proteome scores at day 15 correlated with IEL frequency and with serum IL-2 levels measured 4 hours post gluten intake. Conclusion Biopsy proteome scoring is a simple and reliable measure of gluten-induced mucosal remodeling in response to 14-day oral gluten challenge.