Several studies have linked centrilobular necrosis (CN) to acute cellular rejection (ACR) following liver transplantation. However, it may be difficult to establish the diagnosis of ACR when the classic portal features are absent. The aim of the present study was to identify specific features that would help to recognize ACR in biopsies with CN. One hundred and forty liver biopsies with CN were identified from 97 patients who underwent liver transplantation. The following histopathologic features were assessed: CN, steatosis, lobular inflammation, cholestasis, endothelialitis, and fibrosis. CN was graded semiquantitatively. A number of clinical and biochemical parameters were also recorded. Biopsies with CN were assessed for the presence or absence of ACR and divided into two groups accordingly. The associations of the biochemical, pathologic, and clinical features with ACR were assessed using a multivariate logistic regression model. The outcomes of patients with and without rejection were compared using the Cox proportional hazards regression model. Seventy-four biopsies (52.9%) showed evidence of ACR, and 52 patients (53.6%) had evidence of ACR at the first biopsy with CN. The multivariate analysis showed the presence of cholestasis, lobular inflammation, the ALT level, and time since liver transplantation to be independent predictors of the presence of ACR in biopsies with CN. Patients with ACR on their first biopsy with CN were significantly more likely to experience graft loss compared with patients without ACR. In conclusion, the presence of cholestasis and lobular inflammation on biopsies with CN appeared helpful in predicting its association with ACR.