Background: Reduced D antigen on red blood cells (RBCs) may be due to “partial” D phenotypes associated with loss of epitope(s) and risk for alloimmunization or “weak” D phenotypes that do not lack major epitopes with absence of clinical complications. Genotyping of samples with weak and discrepant D typing is recommended to guide transfusion and RhIG prophylaxis. The goal was to compare the impact of RHD genotyping on transfusion practice in two centers serving different populations. Study Design and Methods: Fifty-seven samples from Denmark and 353 from the United States with weak or discrepant D typing were genotyped. RBC typing was by multiple methods and reagents. DNA isolated from white blood cells was tested with RBC-Ready Gene D weak or CDE in Denmark or RHD BeadChip in the United States. RHD was sequenced for those unresolved. Results: Of Caucasian samples from Denmark, 90% (n = 51) had weak D types 1, 2, or 3; two had other weak D, two partial D, and two new alleles. In diverse ethnic U.S. samples, 44% (n = 155) had weak D types 1, 2, or 3 and 56% (n = 198) had other alleles: uncommon weak D (n = 13), weak 4.0 (n = 62), partial D (n = 107), no RHD (n = 9), and new alleles (n = 7). Conclusion: Most samples with weak or variable D typing from Denmark had alleles without risk for anti-D. In U.S. samples, 48% could safely be treated as D+, 18% may require consideration if pregnancy possible, and 34% could potentially benefit from being treated as D–. Black and multiracial ethnicities were overrepresented relative to population.