The Williams-Beuren syndrome (WBS) region at 7q11.23 is subject to several genomic rearrangements, one of which, the WBSinv-1 variant, is an inversion polymorphism. The WBSinv-1 chromosome has been shown to occur frequently in parents of individuals with WBS, implying that it predisposes the region to the WBS deletion. Here we investigate two WBS families with multiple affected children, and show that in one family, both siblings have a deletion on a WBSinv-1 chromosome background that arose due to interchromosomal recombination. These results suggest that the two WBS deletions in this family were independent events, and that there is likely a significant increase in the risk of deletion of the WBS region associated with the WBSinv-1 chromosome. The rarity of multiplex WBS families would suggest that the overall risk of having a child with WBS is still relatively low; however, families with an existing member with WBS may choose to opt for WBSinv-1 testing and genetic counseling.