The treatment of corticosteroid-resistant or dependent primary immune thrombocytopenia (ITP) remains a clinical challenge. This study aims to evaluate the efficacy and safety of eltrombopag (Elt) in combination with cyclosporine A (CsA) in adults with primary ITP who are corticosteroid-resistant or dependent. This prospective phase II trial enrolled 28 patients from December 2020 to December 2023. All patients fulfilled the diagnostic criteria for ITP and were refractory to prior glucocorticoid (GC) therapy, defined as meeting at least one of the following criteria: (1) GC-resistant (failure to respond to both standard-dose prednisone and high-dose dexamethasone regimens); (2) GC-dependent (relapse during tapering or after discontinuation of GCs). The patients were administered combination therapy consisting of Elt with an initial dose of 50 mg taken nightly, and CsA at a dosage of 3-5 mg/kg/day targeting a trough concentration of 150-250 µg/L, with dose adjustments made in accordance with platelet counts. Efficacy was evaluated at the 8-week mark, with a response defined as a platelet count of ≥ 30 × 10⁹/L and a two-fold increase from baseline, in the absence of bleeding that required clinical intervention. Patients who achieved a response continued with maintenance therapy with the same regimen. Among the 25 evaluable patients, 92.0% (23/25) achieved a response (platelet count ≥ 30 × 10⁹/L), with 72.0% (18/25) attaining a complete response (platelet count ≥ 100 × 10⁹/L). The median time to response was 14 days, the median bleeding score decreased from 2.0 to 1.0, and 78.3% (18/23) maintained remission. Adverse events were systematically evaluated using the Common Terminology Criteria for Adverse Events version 5.0. The most frequently observed adverse events included gingival hyperplasia (60.7%, predominantly Grade 1), hirsutism (35.7%, all Grade 1), and infections (10.7%, including two fatal cases). The combination of Elt and CsA shows rapid and durable efficacy in adults with corticosteroid-resistant or dependent ITP, but necessitates careful monitoring for CsA-related toxicities and infections, contributing to clinical treatment of adult refractory ITP patients. This trial was registered in the Chinese Clinical Trial Registry under the number ChiCTR2000040991.