Background: Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is an emerging disease with grim prognosis. Objective: Our aim was the analysis of prognostic factors, long-term outcome and risk of tumour development in SSC-CIP compared with primary sclerosing cholangitis (PSC) patients. Methods: Retrospective analysis between 2008 and 2018. Results: One hundred and eleven patients with SSC-CIP and 408 PSC patients were identified. Median orthotopic liver transplantation (OLT)-free survival was 16 months for SSC-CIP and 147 months for PSC (p < 0.001). OLT was performed in 18/111 SSC-CIP compared with 166/408 PSC patients (p < 0.001). Malignant tumours were detected in 17.9% of PSC patients (73/408) compared with 2.7% (3/111) in SSC-CIP (p < 0.001). In multivariate Cox regression analysis low levels of C-reactive protein (hazard ratio 4.687 (95% confidence interval (CI) 1.144–19.199, p = 0.032) were significantly associated with a prolonged survival whereas higher age (hazard ratio 0.488 (95% CI 0.23–1.038), p = 0.062) showed a trend for shorter survival in SSC-CIP. For PSC malignancies (hazard ratio 0.42 (95% CI 0.313–0.575), p < 0.001) and higher age (hazard ratio 0.709 (95% CI 0.544–0.922), p = 0.01) were associated with a shorter OLT-free survival. Conclusion: SSC-CIP is characterized by acute onset of liver disease and poor prognosis but with lower tumour incidence compared with PSC.