Innovative treatment strategies for acute graft-versus-host disease (aGVHD) have not replaced corticosteroids as the primary therapy. We retrospectively reviewed 74 patients who received equine antithymocyte globulin (ATG) in addition to corticosteroids as therapy for GVHD, 21 who received primary therapy and 53 who received ATG after progressing or failing to improve with corticosteroids alone. The groups were comparable in clinical characteristics and in timing and severity of GVHD. After primary therapy with ATG 67% of patients' GVHD symptoms were stable or improved by 28 days versus 56% in those receiving secondary ATG (p = 0.57). In univariate analysis the absence of multiple organ, GI, and liver aGVHD and a clinical stage score < or = 4 were predictive of a favorable response, while in a multivariate logistic regression model only a clinical stage score < or = 4 was independently associated with a favorable response (odds ratio 0.08, 95% CI 0.02-0.32, p = 0.003). ATG response rates and 6-month survival (38 vs. 40%, p = 0.89) were similar following primary and secondary ATG. Patients stable or improved 28 days after ATG therapy had a significantly better 6-month survival than those whose aGVHD had progressed (50 vs. 30%, p = 0.02). Further study is required to assess whether some initial presentations of aGVHD would predictably fail corticosteroid therapy and may thus suggest a role for ATG in the primary management of aGVHD. For this determination, formal prospective comparative trials are needed.