Background/Objectives: Eltrombopag, a thrombopoietin receptor agonist, is widely used in the treatment of relapsed or refractory (R/R) immune thrombocytopenia (ITP). This study aimed to compare the efficacy, safety, and tolerability of generic eltrombopag (Rompag®) with original eltrombopag (Revolade®) in adult patients with R/R ITP. Methods: In this prospective, multicenter study conducted at 10 centers, 104 adult ITP patients were followed for at least 3 months. A total of 35 (33.7%) patients received Rompag® and 69 (66.3%) received Revolade®. The primary endpoint was platelet (PLT) response, defined as achieving a PLT count ≥50 × 109/L and at least a twofold increase from baseline, without the need for rescue therapy or transfusion. Secondary endpoints included bleeding rates, fatigue-related quality of life, adverse events (AEs), and rescue therapy requirements. Results: PLT response was achieved in 94.2% of patients in the Revolade® group and 85.7% in the Rompag® group (p = 0.16). Bleeding rates decreased significantly in both groups (Revolade®: 56.5% to 2.9%, p < 0.001; Rompag®: 62.9% to 2.9%, p < 0.001). Although overall AE rates were similar (30.4% in the Revolade® group and 42.9% in the Rompag® group; p = 0.22), arthralgia (28.6% vs. 7.2%, p = 0.01) and vomiting (11.4% vs. 0%, p = 0.008) were more frequent with Rompag®. Conclusions: Both generic and original eltrombopag demonstrated no statistically significant difference in efficacy in achieving PLT response, reducing bleeding, and improving fatigue-related quality of life in adult patients with R/R ITP. Although minor differences in AE profiles were observed, particularly arthralgia and vomiting, both formulations showed acceptable safety and tolerability.