Purpose <p>Transsphenoidal surgery (TSS) is the treatment of choice for Cushing’s disease (CD). In experienced pituitary centers a high remission rate is reported. Nevertheless, endocrinologists and neurosurgeons face cases with persistent or recurrent CD. In addition to medical treatment, radiation therapy and bilateral adrenalectomy, repeat TSS must also be considered. This study evaluates outcomes and predictors of remission following repeat TSS in patients with CD.</p> Methods <p>A retrospective single-center analysis was conducted including all patients who underwent re-TSS for persistent (<i>n</i> = 29) or recurrent (<i>n</i> = 42) CD between 2004 and 2024. Clinical, radiological, intraoperative, and biochemical data were analyzed for factors influencing remission and long-term outcome.</p> Results <p>Remission was achieved in 75.4% at first follow-up and 55.7% at long-term follow-up; early/long-term remission was 70.8%/50.0% after surgery for persistence and 78.4%/59.5% after surgery for recurrence. First reoperation yielded higher remission than those with ≥ 2 prior surgeries (81.6% vs. 50.0%, <i>p</i> = 0.030). Invasive tumor growth was strongly associated with reduced remission (<i>p</i> = 0.001). Selective adenomectomy or adenomectomy with rim excision achieved the highest early remission, whereas subtotal or purely explorative resections were less effective (<i>p</i> = 0.011), indicating that targeted resection of an identifiable lesion improves outcome. Postoperative complications occurred in 14.1% (10/71); major complications in 8.5% (6/71); there was no perioperative mortality.</p> Conclusion <p>Repeat TSS is a safe and effective treatment for both persistent and recurrent CD in specialized pituitary centers. Surgical success depends on tumor invasiveness, prior operations, and surgical strategies. Reoperation should be considered an essential part of individualized, multidisciplinary management to achieve sustained remission.</p>