Heterozygotes for cleidocranial dysplasia (Ccd) and short digits (Dsh) were crossed to test whether synergistic interactions occur between different dominant mutations whose individual pleiotropic phenotypic effects exhibit a common feature. These unlinked mutations are homozygous lethal, and they are congenic on the C57BL/10 background. Each mutation caused more than 10 different anomalies and showed variable expressivity. Each mutation produced several malformations that were present in every heterozygote. Seven different synergistic interactions were found, including one that yielded an entirely new abnormality not predicted from any abnormalities found in either of the single heterozygotes. Although synergistic interactions between dominant mutations have not, to our knowledge, been described in humans, these findings in mice increase the probability that they occur in humans. Under certain circumstances in human populations, the segregation of mutations causing synergistic interactions of the type demonstrated might be confused with recessive inheritance. It will be important to learn whether synergistic interactions can occur between other mutations. If they can, it will probably become important to take synergistic interactions into account when estimating the genetic hazards to humans from mutagens. Three antagonistic interactions were also found.