We present the case of a 55-year-old Colombian male who showed a discrepancy in the serological typing of the RhD antigen in his first platelet donation. The discrepancy persisted after a serological investigation with multiple Anti-D monoclonal reagents (IgG and IgM) under different conditions (22°C and 37°C, saline, and LISS/Coombs). Furthermore, partial RhD typing was performed, obtaining negative results with a commercially available panel of six Anti-D reagents. Molecular analysis showed a homozygous deletion of RHD and heterozygosity for the Crawford variant (RHCE*ce, RHCE*ceCF), with a predicted phenotype of C–, c+, E–, e+, Vs+, V+. Following the investigation of this case, this man has made 14 platelet donations showing variable reactivity, with agglutinations ranging from – to 2+. Since Crawford red blood cells express some RhD antigen epitopes, they could cause alloimmunization in RhD negative receptors. Likewise, Anti-D alloantibodies have been documented in Crawford variant carriers. Therefore, it is recommended that carriers of this variant be classified as RhD positive if they are blood donors and RhD negative if they are transfusion recipients. Also, in pregnant women carrying a Crawford variant, Anti-D immunoprophylaxis is recommended.