Acute graft-versus-host disease (aGVHD) is a major life-threatening complication of allogeneic hematopoietic cell transplantation. While most studies report therapy-response of aGVHD including a cumulative grade of skin, liver and intestinal tract manifestations, there is a lack of information specifically on lower gastrointestinal tract aGVHD (GI-GVHD) therapy-response, which is highly relevant in light of novel therapies that target intestinal regeneration such as IL-22, R-spondin or GLP-2. Here we retrospectively analyzed patients who developed GI-GVHD over a 6-year period. A total of 144 patients developed GI-GVHD and 82 (57%) were resistant to glucocorticoid-therapy (SR). The most commonly used second-line therapy was ruxolitinib (74%). Overall and complete response (CR) to ruxolitinib on day 28 were 44.5% and 13%, respectively. SR-GVHD patients experienced a lower 5-year overall survival (OS) (34.8 vs 53.3%, p = 0.0014) and higher incidence of 12-months non-relapse-mortality (39.2 vs 14.3%, p = 0.016) compared to glucocorticoid-sensitive patients. SR-GI-GVHD patients, that achieved a CR on day 28 after ruxolitinib start, experienced a higher OS compared to non-CR patients (p = 0.04). These findings indicate that therapy response of SR-GI-GVHD to different immunosuppressive approaches is still low, and that novel therapies specifically aiming at enhanced intestinal regeneration should be tested in clinical trials.