Background: Diabetes Mellitus (DM) is a major cause of morbidity and mortality affecting millions of people worldwide, while placing a noteworthy strain on public health funding. There is limited information regarding the determintants of the quality of life of diabetic patients with neuropathy in Greece. Aim: The aim of this study was to assess health-related quality of life (HRQoL) of Greek Type-II DM patients with diabetic neuropathy (DN) and to identify significant predictors of the disease in this patient population. Method and Material: A random sample of 53 patients with DN drawn from two major hospitals in Greece was assessed. Assessment included: demographic characteristics, the SF-12 to calculate physical and mental component summary scores, the Michigan Neuropathic Screening Instrument, Depression-Anxiety-Stress Scale and a pain scale (0-10) for pain assessment. Scale scores were compared with parametric t-test and ANOVA ,and multivariate stepwise linear regression analyses were used to investigate the effect of sociodemographic and diabetes-related variables on HRQoL. Results: The majority of the participants had poor Health-Related quality of Life (HRQoL), with physical component score (PCS) (M=34.4±11.5) and mental component score (MCS) (M=41.4±13.9). The most important predictors of impaired HRQoL were Michigan Neuropathy Screening Instrument, HbA1c, reduced activity, mental fatigue, depressive feelings, neuropathy treatment and coronary artery disease. Older age, lower education, being unmarried, retinopathy, peripheral arterial disease, depression comorbidity, stress and anxiety, were also associated with impaired HRQoL in at least one SF-12 subscale. Multivariate regression analyses produced models explaining significant portions of the variance in SF-12 subscales, both physical (R2 = 66%) and mental functioning (R2=71%), and also showed that diabetes-related indicators were more important disease predictors, compared to sociodemographic variables. Conclusions: The findings could have implications for health promotion in medical practice in Greece. In order to preserve a good HRQoL in DN, it is important to prevent complications, fatigue and depression, and maintain good glycemic control.