About a quarter of patients with severe aplastic anemia (SAA) remain pancytopenic despite immunosuppressive therapy. We have previously demonstrated that eltrombopag has efficacy in this setting with 44% (11/25) of patients having clinically significant hematologic responses. We now report safety and efficacy data on a further 18 patients and long term follow up on the entire cohort of 43 patients. The overall response rate was 17/43 (40%) at 3-4 months, including tri and bi-lineage responses. The majority of patients who remained on eltrombopag in an extension study (14/17) continued to show improvement, and 7 eventually had significant increases in neutrophil, red cell and platelet lineages. Five patients with robust near-normalization of blood counts had drug discontinued at a median of 28.5 months after entry (range 9 to 37), and all maintained stable counts a median of 13 months (range 1-15) off eltrombopag. 8 patients, including 6 non-responders and 2 responders, developed new cytogenetic abnormalities on eltrombopag, including 5 with chromosome 7 loss or partial deletion. None evolved to acute myeloid leukemia to date. Eltrombopag is efficacious in a subset of patients with aplastic anemia refractory to IST, with frequent multilineage responses, and maintenance of normalized hematopoiesis off treatment. This study is registered at www.clinicaltrials.gov, identifier: NCT00922883.