Diabetes is a complex multi-factorial, chronic metabolic illness characterized by hyperglycaemia, due to lack of insulin secretion, insulin action or both. Type 2 diabetes mellitus (T2DM) remains a public health problem in low and middle-income countries, including Ethiopia. Association of ABO-Rh blood group system and diverse diseases including diabetes has been examined in several susceptibility and population genetics studies with inconclusive results. Thus, a study was designed to investigate the phenotypic and allelic distribution of ABO and Rh groups and its possible association with T2DM among follow up cases and health controls attending at Injibara General Hospital, Awi Zone, Northwest Ethiopia. Data on socio-demographic, family history of diabetes BMI, alcohol drinking habit and complications related to T2DM were gathered from a total of 362 individuals, 181 patients and 181 were health controls, via interview using a structured questionnaire and patients‘ records. The ABO- Rh blood groups and glycemic levels of both cases and controls were also determined. The data was entered and analyzed using SPSS version 20.0. ABO allelic frequencies were determined using the Bernstein method. Differences in phenotypic distribution of blood groups were assessed using the chi-square test and P values less than 0.05 for all analyses were considered statistically significant. Most of T2DM cases were 45 years old or more with mean age of 50.82 (+ 12.40) and minimum and the maximum of 18 and 80 years old. Overall, blood group phenotypes O, Rh (+), and allele O were the most frequent while blood group AB, Rh (-) and allele B were the least represented in the studied population. Blood group A was the predominant in T2DM cases while blood group O the most frequent in health controls (p<0.05). Significantly higher percentages of the cases were overweight, former alcoholic and had family history of diabetes than healthy individuals. Age, ABO blood groups, family history, BMI, and alcohol drinking habits were found to be independent determinants of T2DM. However, the variables, sex, education, monthly income, occupation, marital status, glycemic level, and Rh factor were not associated with diabetes. This study suggests that people with the A and B blood groups have a higher risk of developingT2DM, but blood type O have a lower risk of T2DM. Therefore, blood group should be investigated in future clinical and epidemiological studies on diabetes and further pathophysiological research is needed to determine why individuals A and B blood groups have a higher risk of developing T2DM and blood type O have a lower risk of T2DM. Key words/Phrases; ABO-Rh Blood group, Socio-demographic factors, Type-2 diabete