Background: A big variety in blood group distribution can be seen in some geographic regions, as well as, in some ethnic and socio-economic groups. Blood groups are, in fact, defined as surface antigens on the erythrocyte cell membrane, and the distribution of the blood groups varies in different regions of the world. Aim: The aim of our study was to investigate blood group distribution (ABO,RhD) in major ethnic groups in the Republic of Macedonia (Macedonian and Albanian population). Materials and methods: A database with total number of 1547 patients were studied. Their blood group (ABO, RhD) was traced using standardized immunohaematological procedure (gel cards technique). Results: The results from our investigation showed that Macedonians and Albanians did not differ very much. Frequency distribution of each blood group within these two populations did not differ significantly between blood groups O, A and B. The difference in the distribution of AB blood group between Macedonians and Albanians was statistically significant (t=2.5163, p=0.01174, p<0.05). The difference in the distribution of RhD positive and RhD negative between Macedonians and Albanians was not statistically significant (t=-0,6034, p=0,5485, P>0,05). The difference in the distribution was found to be statistically significant between Macedonians and Albanians only in the AB(+) blood group (t=-2,5156, p=0,01174, p<0,05). Conclusion: The only significant difference was found in the distribution of AB blood group (more precisely AB negative), which, in general, is more frequent in Albanian population