Polycomb-group (Pc-G) proteins ensure late maintenance of transcriptional repression outside the expression domain of target genes in flies and vertebrates. They act in complexes, presumably by modulating chromatin structure. In Drosophila , they have been found to be associated with transcriptionally inactive loci but seem to be present in association with actively transcribed promoters as well, a feature which is not yet understood. In the mouse, mutations in several Pc - G genes result in an often subtle, local derepression of only a subset of the Hox genes rostral to their expression domains. We report here that Hox /reporter fusion genes, either randomly integrated as transgenes or as insertions within endogenous loci, are transcriptionally silenced in two mouse Pc - G -null mutants, Mel18 and rae28 . Transcriptional silencing of Hox /reporter transgenes in Pc - G mutants was accompanied by increased DNA methylation in the promoter region. Gene silencing was observed at early developmental stages, long before Pc-G and trithorax-group proteins exert their function in maintenance of the Hox patterns. Although all five Hox genes tested as Hox /reporter fusions were silenced in the Pc - G mutants, transcription of the endogenous loci was mildly decreased in a subset of these Hox genes, and Hoxb1 was the most strongly affected. We discuss the possibilities that the observed negative effect of Pc - G mutations on Hox and Hox /reporter expression may reflect a positive involvement of the Pc-G epigenetic repressors in initial Hox gene transcription and that this requirement is exacerbated by the reporter insertion.