Many phenotypic differences exist between Homo sapiens and its closest relatives, chimpanzees, and these differences can arise as a result of variations in the regulation of certain genes common to these closely related species. Human-specific endogenous retroviruses (HERVs) and their solitary long terminal repeats (LTRs) are probable candidates for such a role due to the presence of regulatory elements, such as enhancers, promoters, splice sites, and polyadenylation signals. In this study we show for the first time that HERVs can participate in the specific antisense regulation of human gene expression owing to their LTR promoter activity. We found that two HERV LTRs situated in the introns of genes SLC4A8 (for sodium bicarbonate cotransporter) and IFT172 (for intraflagellar transport protein 172) in the antisense orientation serve in vivo as promoters for generating RNAs complementary to the exons of enclosing genes. The antisense transcripts formed from LTR promoter were shown to decrease the mRNA level of the corresponding genes. The human-specific regulation of these genes suggests their involvement in the evolutionary process. Copyright © 2009, American Society for Microbiology. All Rights Reserved.