Giant cell tumor of bone and giant cell reparative granuloma are benign lesions with prominent giant (multinucleated) cells, and an understanding of the molecular biology and genetics of these lesions will likely aid in more effective treatment. Cherubism is a benign lesion of the maxilla and mandible histologically similar to giant cell tumor of bone and giant cell reparative granuloma. Germline mutations in exon 9 of the gene encoding Src homology 3 binding protein 2 (SH3BP2) occur in most patients with cherubism. We therefore hypothesized SH3BP2 and its putative downstream effector nuclear factor of activated T cells c1 isoform (NFATc1) are highly expressed in sporadic nonsyndromic giant cell lesions and associated with somatic SH3BP2 mutations. We analyzed giant cell lesions for SH3BP2 and NFATc1 expression by RNA blot and/or immunohistochemistry and for exon 9 SH3BP2 mutations. We found the SH3BP2 transcripts and protein were abundantly expressed in giant cell tumors of bone, as well as NFATc1 protein. Sequencing of exon 9 of SH3BP2 was normal in all sporadic nonsyndromic giant cell lesions. Although many multinucleated giant cell lesions of bone share histologic features, the primary genetic defect in cherubism and these other giant cell lesions appears different.