Mammalian genomes encode numerous cis -natural antisense transcripts ( cis -NATs). The extent to which these cis -NATs are actively regulated and ultimately functionally relevant, as opposed to transcriptional noise, remains a matter of debate. To address this issue, we analyzed the chromatin environment and RNA Pol II binding properties of human cis -NAT promoters genome-wide. Cap analysis of gene expression data were used to identify thousands of cis -NAT promoters, and profiles of nine histone modifications and RNA Pol II binding for these promoters in ENCODE cell types were analyzed using chromatin immunoprecipitation followed by sequencing (ChIP-seq) data. Active cis -NAT promoters are enriched with activating histone modifications and occupied by RNA Pol II, whereas weak cis -NAT promoters are depleted for both activating modifications and RNA Pol II. The enrichment levels of activating histone modifications and RNA Pol II binding show peaks centered around cis -NAT transcriptional start sites, and the levels of activating histone modifications at cis -NAT promoters are positively correlated with cis -NAT expression levels. Cis -NAT promoters also show highly tissue-specific patterns of expression. These results suggest that human cis -NATs are actively transcribed by the RNA Pol II and that their expression is epigenetically regulated, prerequisites for a functional potential for many of these non-coding RNAs.