P seudohypoparathyroidism type IB (PHPIB) is characterized by renal resistance to parathyroid hormone (PTH) and the absence of other endocrine or physical abnormalities. Familial PHPIB has been mapped to 20q13, near GNAS1, which encodes G_sα, the G protein α-subunit required for receptor-stimulated cAMP generation. However, G_sα function is normal in blood cells from PHPIB patients, ruling out mutations within the G_sα coding region. In mice G_sα is expressed only from the maternal allele in renal proximal tubules (the site of PTH action) but is biallelically expressed in most other tissues. Studies in patients with Albright hereditary osteodystrophy suggest a similar G_sα imprinting pattern in humans. Here we identify a region upstream of the G_sα promoter that is normally methylated on the maternal allele and unmethylated on the paternal allele, but that is unmethylated on both alleles in all 13 PHPIB patients studied. Within this region is an alternative promoter and first exon (exon 1A), generating transcripts that are normally expressed only from the paternal allele, but that are biallelically expressed in PHPIB patients. Therefore, PHPIB is associated with a paternal-specific imprinting pattern of the exon 1A region on both alleles, which may lead to decreased G_sα expression in renal proximal tubules. We propose that loss of exon 1A imprinting is the cause of PHPIB.