BACKGROUND: D(C)(e) and D(C)e haplotypes may be encountered in the white population. Few data are available on the molecular backgrounds responsible for depressed expression of C and e. STUDY DESIGN AND METHODS: Individuals of white origin carrying a D(C)(e) genotype resulting in depressed expression of C or both C and e were subdivided into two categories based on the RBC reactivity with the human sera Mol and Hor, which contain antibodies against low‐frequency antigens of the Rh (RH) system and other non‐Rh low‐frequency antigens. Neither Hor+, Mol+ nor Hor+, Mol– RBCs expressed the V (RH10), VS (RH20), and/or Rh32 (RH32) low‐frequency antigens. These results suggested that Hor+, Mol+ variants expressed Rh33 (RH33 or Har) and FPTT (RH50), whereas Hor+, Mol– variants might express an undefined low‐frequency antigen. Further serologic and molecular analyses were performed. RESULTS: Molecular analysis of Hor+, Mol+ variants revealed a hybrid gene structure RHCe‐D(5)‐Ce, in which exon 5 of RHCE (RHCe allele) was replaced by exon 5 of RHD (the so‐called RHCeVA allele). The presence of exon 5RHD resulted in several amino acid alterations predicted in the external loop 4 of the CeVA polypeptide. Molecular analysis of Hor+, Mol– variants revealed the presence of a new RHCe allele characterized by a single point mutation C340T within exon 3 (the so‐called RHCeMA allele), resulting in a R114W substitution predicted on the external loop 2 of the CeMA polypeptide. A serologic study showed a different pattern of reactivity with C and e MoAbs. CONCLUSION: Two types of mutations resulted in amino acid substitutions predicted in external loops 4 and 2, respectively, which altered both the C and e reactivity, and indicated conformation changes or defective interaction between nonadjacent loops of the Ce polypeptide. Serologic analysis showed that together with Hor and Mol sera testing, the use of different C and e MoAbs could help to identify these variants within the white population.