Sizable homozygous deletions (>100 bp) of genomic DNA in cancer cells are typically interpreted as an indication of the location of a tumor suppressor gene. In an effort to identify novel ovarian growth-suppressing genes, we performed representational difference analysis (RDA) of ovarian cancer cells. One of the RDA probes identified a 276-bp region of chromosome 22q deleted in 47% of the ovarian cancer cell lines examined. This small deletion was also found in the genomic DNA of 25% of colon cancer cell lines examined and, surprisingly, in 18% of the blood DNA samples from healthy controls. The deleted allele, which was named u22q, has a frequency of approximately 50% in the population and is in Hardy–Weinberg equilibrium with the intact allele. The deleted DNA sequence is flanked by direct repeats and likely originated through a slipped mispairing mechanism. The deletion did not encompass known transcripts or expressed sequence tags. It therefore appears likely that u22q represents a common polymorphism, often hemizygous in ovarian cancer because of a high rate of LOH of chromosome 22q. These findings provide an example of a sizable homozygous deletion that does not appear to be associated with disease. Such a finding provides a cautionary tale for positional cloning projects initiated exclusively on the basis of the identification of homozygous deletions. The possibility that the deletions in question may be constitutive should always be considered since it is probable that the genome contains a large number deletions/insertions of various sizes.