INTRODUCTION: Primary Sclerosing Cholangitis (PSC) is a chronic, immune-mediated cholestatic liver disease with a strong association with Inflammatory Bowel Disease (IBD), including Crohn’s disease (CD). Our group has shown that patients with CD have twice the risk of hepatic steatosis compared to the general population. We have also shown that there is a robust protective effect of ileal-inflammation and hepatic steatosis in CD. Conversely, we found active perianal disease increases the risk of hepatic steatosis. These findings suggest that inflammation directed through the portal vein is protective against hepatic steatosis. In this study, we aimed to demonstrate if an analogous inflammatory marker in PSC, alkaline phosphatase, is protective against hepatic steatosis. METHODS: This is a single-center, retrospective cohort study between 1/1/2013 through 12/31/2018. Adult patients with a clinical diagnosis of PSC that had undergone magnetic resonance cholangiopancreatography (MRCP) were included. Patients with an alternative etiology of liver disease (e.g. chronic viral hepatitis, greater than moderate alcohol use) were excluded. All MRCP protocols had been modified to allow liver fat quantification by the proton density fat fraction (PDFF) method. The primary outcome was the nonparametric, Spearman’s correlation (Rs) between PDFF and alkaline phosphatase. Secondary analysis was performed using a linear regression model for the natural log (Ln) transformation of PDFF. RESULTS: There were 112 PSC patients (80% with Ulcerative colitis, median age at enrollment 48 years, median age at PSC diagnosis 39 years). The median PDFF was 2.3% and the median body-mass index (BMI) was 27 kg/m2. There was a negative-linear relationship between PDFF and alkaline phosphatase with a Rs = 0.4 (P < 0.001). This negative-linear relationship between alkaline phosphatase and PDFF persisted after adjusting for BMI in the linear regression model (P < 0.001). CONCLUSION: We demonstrated that alkaline phosphatase, the surrogate for PSC-associated cholestasis and hepatic inflammation, demonstrates a negative-linear relationship with liver fat even after adjusting for BMI. This supports the hypothesis that acute inflammation in the portal circulation is protective against hepatic steatosis. Future directions include clarifying the role of the enterohepatic circulation and non-immunologic enterokines in liver-fat handling.