BACKGROUND The understanding of blood group phenotypes in Saudi Arabia is limited to the ABO and Rh blood groups. Data for the other major blood group phenotypes in different populations have been widely studied and used as a reference for identifying antigen-negative blood in hospital blood banks. Such information is crucial for facilitating the challenging task of providing antigen-negative blood for patients with multiple antibodies. OBJECTIVE The aim of this study was to determine the frequency of the major blood group phenotypes in the Eastern region of Saudi Arabia and compare them to phenotypes in other populations. METHODS A total of 100 volunteer Saudi donors were included in this study. Red blood cells from the donors were subjected to antigen typing of the major blood group systems (Rh, Kell, Kidd, Duffy, MNS, Lewis, Lutheran, and P) using the gel microtube technique. RESULTS From the Rh blood group system, the e antigen was found in 97% of donors, followed by c at 86%. The Cellano (k) antigen of the Kell system was found in all donors, whereas the Kell (K) antigen was only found in 8 % of donors. The K+k- phenotype was not detected in our study. Unexpectedly, for the Duffy blood group system, the null phenotype Fy(a-b-) was found in 61% of donors. In the MNS blood group system, M+N-S+s+ was the most common phenotype at 24%. CONCLUSIONS The frequency of blood group phenotypes in the Eastern region of Saudi Arabia differs from that in other populations because of the diverse ethnic backgrounds of those living in that region. The findings of this study can be used to establish a local donor registry to help provide antigen-negative blood for patients with unexpected antibodies or to create an in-house antibody identification panel to add to the commercial panel that would be useful for confirming antibody identification results.