Background & Aim: Gastrointestinal biopsies are common specimens evaluated in surgical pathology departments. Routinely, mucosal specimens are embedded randomly with respect to the side of the biopsy that faces microtome blade. However, sometimes initial histological sections of putative lesions — in spite of strong clinical suspicion — may lack any appreciable pathological findings. This study is designed for comparison between routine resectioning and new-emerging reorienting(or flipping) methods in providing diagnostic information in cases with no histopathological findings. Material & Method: In an analytical cross-sectional study, sixty-three gastrointestinal cases with different clinical impressions whose first slides were devoid of any specific findings were selected. Initially, another H&E(Hematoxylin and Eosin)-stained slide was prepared(labeled as “S” for resectioning). Then, paraffin-block was melted. Tissue was 180˚ reoriented and reembedded. Two other H&E(Hematoxylin and Eosin)-stained slides were prepared(labeled as “O1” and “O2” for reorienting). The section levels were sequentially arranged on slides and — in cases of changes — the first level on which the new findings were evident was recorded. Results: Overall, 13 out of 63 cases(20.63%) revealed new histopathological changes, including 7 cases(11.1%) with essential changes and 6 cases(9.5%) with non-essential changes. Resectioning and reorienting methods displayed new findings in 8 cases(61.5% of all changed cases) and 7 cases(53.8% of all changed cases) respectively. Two cases(about 15.4%) were common in both groups. In cases of changes, all new findings developed in the fifth resectioning and/or the first reorienting level. Conclusion: Despite lack of significant statistical difference between two methods, emergence of additional diagnostic — and sometimes critical — information in each of the methods makes two-sided sectioning an essential approach in cases of discordance between clinical impressions and histological findings