It has been proposed that the structure of the exons that encode the triple helical domain of the fibrillar collagen genes arose by repeated tandem duplication of an ancestral unit exon. Because these exons encode a repeat motif [(Gly-X-Y)n], sequence homology between exons may have driven the recombinational process. We have characterized a tandem duplication mutation within a COL1A1 allele of type I collagen from an infant with the lethal form of osteogenesis imperfecta. The structure of the mutation is consistent with the occurrence of an unequal crossover within a 15 base pair region of sequence identity between exons 14 and 17 of the COL1A1 gene. The recombination produced a new 81 base pair 17/14 hybrid exon and complete duplication of exons 15 and 16. The sequence implies duplication of 60 amino acid residues within the triple helical domain with preservation of the Gly-X-Y repeat. These data suggest that a recombinational mechanism that explains the hypothetical evolutionary process is active in cells, but the lethal effect of this mutation raises questions about the role of these events in creating new structures for polymeric proteins.