A total of 20,000 parent-offspring transfers of alleles were examined through the genotyping within 40 CEPH reference families of 28 short tandem repeat polymorphisms (STRPs) located on chromosome 19. Forty-seven initial mutation events were detected in the STRPs using DNA from transformed lymphoblastoid cell lines, but less than half (39%) could be verified using DNA from untransformed cells. None of the cases where three alleles were observed In a single Individual could be verified using DNA from untransformed cells. The average mutation rate for the chromosome 19 STRPs after correction for events which would not be detectable as Mendelian errors was 1.2 × 10−3 per locus per gamete per generation. This rate may have been Inflated by somatic as opposed to germline events. Observed mutation rates for individual STRPs ranged from 0 to 8 × 10−3. The average mutation rate for tetranucleotide STRPs was nearly four times higher than the average rate for dinucleotide STRPs. For determination of the mode of mutation, events Involving STRPs on other chromosomes were also examined. Of the events which were verified using DNA from untransformed lymphocytes or which were likely among those for which DNA from untransformed cells was not available: none were located at the sites of melotic recombination, 91% Involved the gain or loss of a single repeat unit, and 15 occurred In the male germline compared to 4 in the female germline (p = 0.01).