Background: ABO blood group has been found to be associated with the risk of several malignancies, including gastric cancer, pancreatic cancer, ovarian epithelial and skin cancer. This work was therefore aimed at assessing the ABO and Rh blood group antigens and risk associated with human immunodeficiency virus (HIV) infection among blood donors. Materials and methods: This is a retrospective cross-sectional analytical study carried out in the department of Transfusion Medicine of a tertiary care teaching hospital blood bank for a period of 6 years i.e. January 2009 to December 2014. All blood donors either voluntary or replacement were included in the study. Data retrieved from blood bank records included the ABO, Rh group and the result of HIV serology. Statistical analysis was carried out using SPSS version 16, SPSS Inc, Chicago, USA. Results: A total number of 41652 blood donors were registered and screened during the study period. The commonest blood group was O constituting 41.5% followed by B (32.6%), A (19.8%), AB (6.1%) and Bombay (0.02%). Rh-D positive donors were 92.9% and remaining 7.1% were Rh-D negative. The overall prevalence of HIV was 0.66%. Among total HIV seroreactive donors 42.6% were O blood group, B-27.8%, A-22.2% and AB-7.4%. Among the total seroreactive group, 93.5% had Rh-D positive blood group and remaining 6.5% had Rh-D negative blood group. Conclusion: In this study conducted to determine the predominant blood group antigen and its association with HIV seroreactivity. The frequency of HIV among blood donors had maximum association with blood group O positive but not statistically significant. Larger scale studies at molecular level are required to improve the knowledge of this aspect.