We reviewed liver histologic results from all allogeneic hematopoietic stem cell transplant recipients from our institution with a confirmed diagnosis of liver graft-versus-host disease (L-GVHD), no concomitant causes of liver dysfunction, and at least 1 diagnostic liver biopsy sample (n=33) to ascertain whether histologic features predicted clinical outcome. The 1-year probability of nonrelapse mortality (NRM) from the onset of liver dysfunction was 68.15%, with a median overall survival (OS) of 6.2 months for the entire group. Histologic features traditionally linked to the diagnosis of L-GVHD (eg, bile duct damage, bile duct lymphocytic infiltration, portal inflammation, and ductopenia) had no association with patient outcome. However, an extended histologic analysis showed that a high level of lobular inflammation (LI) and a low level of hepatocyte ballooning (HB) were independent favorable prognostic factors for NRM (RR, 5.14; P=.033; and relative risk (RR), 0.18; P=.018, respectively) and OS (RR, 3.99; P=.032; and RR, 0.23; P=.037, respectively). The presence and severity of LI and HB were not associated with patient- or transplant-related characteristics or L-GVHD clinical factors such as timing of the biopsy from the onset of L-GVHD, acute versus chronic presentation, or whether the patients had started immunosuppressive treatment with steroids at the time of the biopsy. In multivariate analysis that included clinical prognostic factors, the combined histologic risk posed by high LI and low HB retained independent favorable prognostic value for NRM (RR, 5.05; P=.015) and OS (RR, 3.31; P=.038). This information, if replicated in other studies, could expand current indications for liver biopsy in patients with L-GVHD, not only to exclude other causes of liver injury, but also to predict clinical outcome, and should be considered in the selection of patients and the design of future trials with new experimental therapies for this complication. Prospective validation of our findings is warranted.