The ability to correlate chromosome conformation and gene expression gives a great deal of information regarding the strategies used by a cell to properly regulate gene activity. 4C-Seq is a relatively new and increasingly popular technology where the set of genomic interactions generated by a single point in the genome can be determined. 4C-Seq experiments generate large, complicated data sets and it is imperative that signal is properly distinguished from noise. Currently, there are a limited number of methods for analyzing 4C-Seq data. Here, we present a new method, fourSig, which in addition to being precise and simple to use also includes a new feature that prioritizes detected interactions. Our results demonstrate the efficacy of fourSig with previously published and novel 4C-Seq data sets and show that our significance prioritization correlates with the ability to reproducibly detect interactions among replicates.