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Background: Transmural healing (TH) is being increasingly recognized for reflecting deep remission in Crohn's disease (CD). The long-term clinical significance of achieving TH is still not fully known. We aimed to evaluate TH as a predictor of long-term positive outcomes using intestinal ultrasonography (US), with comparison with the established endpoint mucosal healing (MH). Methods: CD patients were consecutively recruited from September 2015 to August 2018 at a single tertiary hospital. All patients were evaluated at baseline and followed up at 6 months prospectively with a guideline-based treatment regimen. Achieving TH/MH or not was evaluated by US/colonoscopy at the first follow-up. Long-term outcomes including steroid-free clinical remission (CR), drug escalation, hospitalization, and surgery, were recorded after at least another 12 months. Results: We identified 77 patients with a median age of 30 years (range, 12–73 years). Twenty-five (32%) patients achieved TH, and 31 (40%) patients achieved MH. TH and MH were poorly correlated (Cohen's κ = 0.387; p < 0.05). Univariate analysis showed that both MH and TH were associated with better long-term outcomes. In multivariate analysis, TH was an independent predictor of steroid-free CR [odds ratio (OR), 52.6; p < 0.001], drug escalation (OR, 0.1; p = 0.002), and hospitalization (OR, 0.05; p = 0.005), while MH was an independent predictor of drug escalation (OR, 0.3; p = 0.05). Smoking habit was the only predictor of surgery (OR, 6.6; p = 0.02). Conclusion: TH is an independent predictor of more favorable long-term outcomes than MH, suggesting that TH could become the potential treatment endpoint in CD. Plain language summary: Transmural healing predicts good prognosis in Crohn's disease The therapeutic endpoints of Crohn's disease keep evolving. The long-term clinical significance of achieving transmural healing is not fully discovered. Transmural healing is an independent predictor of more favorable long-term outcomes than mucosal healing. Transmural healing could become the potential treatment endpoint in Crohn's disease. [ABSTRACT FROM AUTHOR]