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Graft-versus-host disease (GVHD) is a principal cause of morbidity and mortality following allogeneic hematopoietic cell transplant (HCT). Standard therapy for GVHD, high dose steroids, results in complete responses in only 35% of patients. Because tumor necrosis factor-α (TNFα) is an important effector of GVHD in animal models we treated 61 pts with new onset GVHD with methlyprednisolone 2 mg/kg/d plus etanercept, a TNFα inhibitor. All pts continued their GVHD prophylaxis agent, usually tacrolimus, at therapeutic dosing. Etanercept was given subcutaneously twice weekly for 8 wks at a dose of 0.4 mg/kg/dose (maximum dose 25 mg). The outcomes in these 61 pts were compared to those of 99 contemporaneous pts with GVHD whose initial therapy was steroids alone. Both groups of pts were similar with respect to age, transplant conditioning intensity, donor type and degree of HLA-match, and severity of GVHD at onset. Pts treated with etanercept plus steroids were significantly more likely to achieve a complete response 4 wks later than were pts treated with steroids alone [69% (95% CI: 57%, 81%) vs 33% (95% CI: 24%, 42%), p Pts treated with etanercept plus steroids were significantly more likely to be alive 100 days from the initiation of GVHD treatment than pts treated with steroids alone (82% vs 66%, p=0.04). The infection rates in the first 100d from initiation of GVHD treatment were not different between pts treated with etanercept plus steroids or treated with steroids alone for bacterial, invasive fungal or viral infections Blood samples obtained at onset of GVHD and four wks later were analyzed for plasma levels of TNF-receptor 1 (TNFR1) as a biomarker of GVHD activity. At the onset of GVHD the mean plasma TNFR1 levels were significantly elevated compared to levels at a similar timepoint from a control group of pts without GVHD; 4 wks later mean plasma TNFR1 levels were decreased significantly only in pts with CR. Although not a randomized phase III trial, these large differences between treatment groups strongly suggest that etanercept plus steroids as initial therapy for acute GVHD results in improved complete response rates compared to steroids alone. Figure Figure Complete Response Rates at Four Weeks According to Treatment Group Steroids alone Etanercept plus steroids p value Overall 33/99 (33%) 42/61 (69%)