The imprinted UBE3A gene exhibits maternal-only expression in specific cell types in the brain, but exhibits biallelic expression in other cell types. UBE3A is located adjacent to a cluster of imprinted, paternally expressed genes that are known to be positively regulated by the Prader-Willi syndrome imprinting center (PWS-IC). Here, we examined the effect of the PWS-IC on the UBE3A locus. Using intersubspecific crosses, we found that deletion of the PWS-IC causes an upregulation of the paternal Ube3a allele. This indicates that unlike its positive effect on all the other paternally expressed transcripts in the region, the PWS-IC negatively regulates the levels of paternal UBE3A. Interestingly, we found that like the human UBE3A locus, the murine Ube3a locus includes an imprinted, paternally expressed antisense transcript. We show that this paternal antisense transcript is positively regulated by the PWS-IC. These results are consistent with a model in which the PWS-IC mediates activation and maintenance of paternal gene expression in the 15q11-q13 region, with repression of the paternal UBE3A gene occurring as an indirect result of expression of the antisense transcript.