Background: Diabetes mellitus (DM) has been identified as a new risk factor for hepatocellular carcinoma (HCC) that is also associated with changes of peripheral blood cells. However, no information was available for the relationship between DM and changes of peripheral blood cells. Our present study was designed to determine this relationship in our Chinese HCC patients. Methods: Patients who were diagnosed with HCC and hospitalized at our hospital in the period from January 2003 to April 2012 were included in this study. Their data, including demographic, metabolic, laboratory, biochemical, instrumental, radiological and pathological features, were analyzed. Results: A total of 375 HCC patients were included and 63 (16.8%) of which were diagnosed with diabetes. Compared with patients without DM, the HCC patients with DM were older, and had increased levels of fasting glucose and systolic blood pressure (SBP), lower values of hemoglobin and platelet count, and a lower percentage of patients with HBV infection. Multivariable analysis showed that hemoglobin (OR=0.982; 95% CI, 0.971-0.993; P=0.002) and SBP (OR=1.017; 95% CI, 1.001-1.034; P=0.039) were independently associated with HCC and DM. Considering the effect of cirrhosis and HBV infection for DM, sub-group analyses were performed and similar results were gained for hemoglobin (OR= 0.984, 95% CI=0.970-0.998, P=0.030; OR=0.982, 95% CI=0.969-0.995, P=0.006; respectively). For treatment of diabetes, patients with biguanide use had increased levels of hemoglobin, compared with those without biguanide use. Conclusions: Hemoglobin concentrations may be affected by diabetes in our HCC patients and treatment with biguanide maybe has the potential to prevent this change.