Aim of Study: To assess health-related quality of life (HRQOL) of type 2 diabetic patients in Aseer Region, Saudi Arabia. Methods: Following a case-control research design, this study included 100 adult type 2 diabetic patients and 100 healthy, age- and sex-matched subjects who attended outpatient clinics at primary health-care centers in Aseer Region, Saudi Arabia. Data were collected using an interviewer-administered questionnaire that comprised two parts. The first part covered sociodemographic and clinical data about diabetes, while the second part was the Arabic version of the 12-Item Short Form Survey (SF-12). Results: Diabetic patients had significantly lower SF-12 mean scores than control subjects, as regards the physical and mental components (p<0.001 for both components). Patients' SF-12 physical and mental scores differed significantly according to their age groups, educational status, employment, and monthly income (p<0.001 for all). Female patients had significantly lower scores of mental component (17.6 +/- 3.8 and 19.2 +/- 3.9, respectively, p=0.041). Patients' SF-12 physical and mental scores were lowest among those with higher body mass index. However, scores did not differ significantly according to their body mass index. SF-12 physical and mental scores negatively and significantly correlated with duration of diabetes, fasting blood glucose and HbA1c (p<0.001 for all correlations). Conclusions: Several risk factors can affect the HRQOL of diabetic patients including older age, female gender, level of education, employment, monthly income, marital status, and duration of diabetes.