Human CD1 genes have been reported to be invariant or to show limited polymorphism. Recently, certain functions of CD1 antigens have been described to include the presentation lipid and glycolipid antigens. These observations prompted a thorough survey of the genetic polymorphism in the five human CD1 genes (CD1a–CD1e). Using polymerase chain reaction‐single stranded conformational polymorphism (PCR‐SSCP) combined with sequence analyses, exons 2 and 3 from CD1a–CD1e were characterized from a total of 110 unrelated healthy donors. Results showed that all five genes (CD1a–CD1e) are polymorphic in exon 2. Substitutions in CD1b and CD1c are silent, whereas, substitutions in CD1a, CD1d and CD1e result in amino acid replacements in the deduced protein products. CD1a and CD1e polymorphisms are prevalent in the population. The substitutions in CD1a have characteristics that may influence interactions with β₂‐microglobulin (β₂‐m) or accessory molecules. The substitution in CD1e is located in the region predicted to interact with ligands and may differentially impact the ability of CD1e alleles to bind antigen.