There is no consensus on the optimal treatment of steroid-refractory acute graft-versus-host disease (SR-aGVHD) after allogeneic hematopoietic stem cell transplantation. In our center, the treatment policy has changed over time with mycophenolate mofetil (MMF) being used from 1999 to 2003, and etanercept or inolimomab after 2004. An observational study compared survival and infection rates in all consecutive patients receiving 1 of these 3 treatments. Ninety-three patients were included. The main end point was overall survival (OS). Median age was 37 years. Acute GVHD developed at a median of 15 days after transplantation. Second-line treatment was initiated a median of 12 days after aGVHD diagnosis. Therapies were MMF in 56%, inolimomab in 22%, and etanercept in 23% of the patients. Overall, second-line treatment response rate was 45% (complete response: 28%), MMF: 55%, inolimomab: 35%, and etanercept: 28%. With 74 months median follow-up, the 2-year survival was 30% (95% confidence interval: 22-41). Risk factors significantly associated with OS in multivariate analysis were disease status at transplantation; grade III-IV aGVHD at second-line treatment institution; and liver involvement. None of the second-line therapy influenced this poor outcome. Viral and fungal infections were not statistically different among the 3 treatment options; however, bacterial infections were more frequent in patients treated with anticytokines. Over an 11-year period, 3 treatment strategies, including 2 anticytokines, give similar results in patients with SR-aGVHD.