Human placental alkaline phosphatase (AP) exhibits a genetic polymorphism that is determined by the genotype of the fetus. A similar enzyme is produced by certain neoplasms and by some cells in culture. The relationships between these enzymes were investigated by immunological methods comparing human placental AP to the AP of HeLa(71) cells. Antiserum prepared against placental AP precipitated 90 percent of the enzyme and the catalytic activity was quantitatively recovered in the antigen-antibody precipitate. Enzyme-antibody complexes failed to migrate on starch gel electrophoresis, Antiserum against placental AP cross-reacted with HeLa(71)AP and HeLa(71)AP antiserum reacted with the placental enzyme. Immunological analysis by double diffusion in agar showed that the three common genetic variants of placental AP - F, FS and s - and the HeLa(71)AP were closely related when studied by antisera against both placental or HeLa(71)AP. When studied by immunodiffusion the genetic variants of human placental AP and the HeLa enzyme reacted with identity at the points of contact of the precipitation lines when precipitated by antisera against either enzyme. These findings support the view that the human placental and HeLa(71)APs are products of the same genetic locus. Derepression of a portion of the genome in association with malignant transformation might be responsible for ectopic production of this enzyme in HeLa(71) cells.