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Severe acute graft‐versus‐host disease (GVHD) is a life‐threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). The placenta protects the fetus from the mother's immune system. We evaluated placenta‐derived decidua stromal cells (DSCs), which differ from bone marrow mesenchymal stromal cells (BM‐MSCs), as a treatment for severe acute GVHD. DSCs were obtained from term placentas. The DSCs were given to 38 patients with severe acute GVHD; 25 were steroid refractory (SR). DSCs were thawed and infused in buffer supplemented with either 10% AB plasma (group 1,  n  = 17), or 5% albumin (group 2,  n  = 21). The viability of cells was higher when thawed in albumin rather than AB plasma ( p  &lt; .001). Group 1 received a higher cell dose ( p  &lt; .001), cells of lower passage number ( p  &lt; .001), and fewer infusions ( p  = .002) than group 2. The GVHD response (no/partial/complete) was 7/5/5 in group 1 and 0/10/11 in group 2 ( p  = .01). One‐year survival in the two groups was 47% (95% confidence interval [CI] 23–68) and 76% (95% CI 51–89), respectively ( p  = .016). For the SR patients, 1‐year survival was 73% (95% CI 37–90) in SR group 2 ( n  = 11), which was better than 31% (95% CI 11–54) in SR group 1 ( n  = 13;  p  = .02), 20% (95% CI 5–42) in BM‐MSC treated ( n  = 15;  p  = .0015), and 3% (95% CI 0–14) in historic controls ( n  = 32;  p  &lt; .001). DSCs are a promising new treatment for severe acute GVHD. Prospective randomized trials are needed for evaluation of efficacy. (Clinical trial NCT‐02172937.)  Stem   Cells   Translational   Medicine   2018;7:325–332

Placenta‐Derived Decidua Stromal Cells for Treatment of Severe Acute Graft‐Versus‐Host Disease