Patients with the most common weak D types 1, 2, and 3 can be safely considered D positive. We evaluated 1,113 Rh-negative Egyptian samples for weak D expression to propose a cost-effective strategy related to D variant testing. D variants were tested using polymerase chain reaction with sequence-specific priming. Fifty samples were D variants (4.5%): weak D type 4.2 (32%), weak D type 4.0/4.1 (16%), and weak D type 15 (2%). Fifteen (62.5%) of 24 samples were identified serologically as partial D. We also studied the probability of the development of anti-D in 52 Rh-negative children with thalassemia who were receiving units for which weak D was not tested. Anti-D alloimmunization was observed in 63.5% of patients with thalassemia. It is prudent to implement weak D typing in Egyptian donors. Weak D variants of Egyptians are significantly different compared with Caucasians. Ethnicity must be taken into consideration when developing clinical and prenatal strategies related to D variants.