Diabetes mellitus (DM) and systemic inflammation are closely associated with the development of hepatocellular carcinoma (HCC). However, the prognostic significance of DM on HCC remains controversial. The main purpose of the present study was to evaluate the effects of DM and the systemic inflammation-based neutrophil to lymphocyte ratio (NLR) on the overall survival (OS) rate of non-viral HCC patients treated with transarterial chemoembolization (TACE). A retrospective analysis of 138 patients with HCC, who were diagnosed between 2002 and 2012 with non-viral causes and who later underwent TACE, was performed. Among these patients, 34 (24.6%) had pre-existing DM and 46 (33.3%) exhibited an elevated baseline NLR (>= 5). The multivariate analysis showed that DM, the NLR and a portal vein tumor thrombus (PVTT) were independent predictors for a poor OS rate (P<0.05). The patients with DM and an elevated NLR exhibited a poorer OS rate when compared with patients without these factors. In addition, there was a significant stepwise improvement in the OS rate of patients with DM and an elevated NLR, and in patients with only one of these factors compared with patients without either (P<0.01). Finally, DM was significantly correlated with PVTT and elevated gamma-glutamyl transpeptidase levels, while the NLR was independently associated with PVTT and tumor multiplicity (P<0.05). The present study revealed that DM, baseline NLR and PVTT are independent indicators of the OS rate in non-viral HCC patients treated with TACE. DM and NLR may affect the OS rate by promoting the malignant progression of HCC. The combination of DM and NLR appears to be a stronger predictor for OS than DM or NLR alone.