Acute graft-versus-host-disease (aGVHD) is the main cause of morbidity and nonrelapse mortality (NRM) following allogeneic hematopoietic cell transplantation (alloHCT). Nausea, vomiting, and anorexia after alloHCT can be early signs of aGVHD of the gastrointestinal tract (GIT) but may also reflect lasting mucosal damage or side effects of drugs. If upper GIT aGVHD is suspected, upper endoscopic evaluation and histological examination are crucial. Still, the interpretation of clinical symptoms, macroscopical alterations, and histological findings can be challenging. Therefore, we conducted a retrospective analysis on single-center data from 174 patients with suspected aGVHD of the upper GIT who underwent upper endoscopy within the first 6 weeks after alloHCT, to study the distribution of aGVHD-related histological findings in relation to clinical symptoms and macroscopic findings and to correlate the severity of changes with data on relapse and NRM. Our data suggest that biopsies of the duodenum reveal the severity of upper GIT aGVHD most accurately. While the histological grading correlated weakly with the severity of macroscopic changes, we found a tight correlation between histological and clinical grades of upper GIT aGVHD (p < 0.001). Although correlation of histological grading of upper GIT aGVHD with the risk for NRM missed statistical significance (HR 1.53, Lerner ≥1° versus <1º, p = 0.13), overall clinical aGVHD severity correlated with NRM (HR 4.3, IIIº–IVº versus 0–Iº, p < 0.01). In conclusion, biopsies from the duodenum are most sensitive in excluding aGVHD in patients with normal macroscopic findings at esophagogastroduodenoscopy. Clinical grading of aGVHD predicts NRM better than histological grading.