Secondary sclerosing cholangitis (SSC) is a chronic cholestatic disorder caused by mechanical, infectious, toxic, or ischemic factors. A new variant of SSC occurring after long-term treatment in intensive care units (ICU) has been recently described and characterized from the clinical point of view. The aim of this study was the histomorphological characterization of ICU-treatment-related SSC (ICU-SSC) and the definition of histological changes occurring over time based on the morphological findings. Liver biopsies of ten patients affected by ICU-SSC obtained at different time points (1.5 to 57 months) after the initial injury were analyzed. The main morphological alterations included degenerative changes of portal bile ducts, portal edema, inflammation, and fibrosis as well as biliary interface activity and bilirubinostasis. Perivenular necroses and bile infarcts were found in eight and six patients, respectively. Bile duct loss was not observed. No correlation between morphological features of biopsies and liver chemistry tests or outcome could be established. Based on the morphological observation, a possible disease-progression model starting with an initial damage of portal bile ducts (primary insult) with associated portal/periportal changes (inflammation, ductular reaction) and resulting in secondary parenchymal changes is proposed.