ABSTRACT: Background:Second-line treatment for immune thrombocytopenia (ITP) is not well reported for patients treated in real-world clinical settings. Objective:The purpose of this study was to compare outcomes of four second-line treatments for ITP. Patients/methods:Included adult patients had at least two medical records containing ITP diagnoses and second-line eltrombopag, romiplostim, rituximab, or splenectomy. Date of treatment initiation or splenectomy was set as index date, between July 1, 2008, and March 31, 2017. Patients had first-line corticosteroid or intravenous immune globulin treatment and continuous database activity from 6 months before to 12 months after index. Patient characteristics, treatment patterns, platelet counts, bleeding-related episodes (BREs), and thrombotic events (TEs) were compared by second-line treatment cohort. Results:The sample included 3332 patients (mean age, 60.5 years; 52.3% female): eltrombopag (5.8%), romiplostim (9.9%), rituximab (73.3%), and splenectomy (11.0%). Patients having splenectomy were younger, more likely female and commercially insured, and less likely to require a third line of treatment than medical regimen cohorts. Proportions of patients having treatment-free (?180 days with no second-line index or rescue agent) periods varied significantly (P = .01) by regimen: 33% for eltrombopag, 23% for romiplostim, 26% for rituximab, and 17% for splenectomy. All regimens significantly improved platelet counts, while TE and BRE rates differed significantly (P = .03 and P = .01, respectively) when all treatment groups were compared. Conclusions:Over an average 7-year follow-up, all second-line regimens improved platelet counts, but eltrombopag yielded the highest proportion of patients with completely treatment-free periods of at least 180 days.