A multi-purpose and flexible k-meric enrichment analysis software. 'kmeRtone' measures the enrichment of k-mers by comparing the population of k-mers in the case loci with a carefully devised internal negative control group, consisting of k-mers from regions close to, yet sufficiently distant from, the case loci to mitigate any potential sequencing bias. This method effectively captures both the local sequencing variations and broader sequence influences, while also correcting for potential biases, thereby ensuring more accurate analysis. The core functionality of 'kmeRtone' is the SCORE() function, which calculates the susceptibility scores for k-mers in case and control regions. Case regions are defined by the genomic coordinates provided in a file by the user and the control regions can be constructed relative to the case regions or provided directly. The k-meric susceptibility scores are calculated by using a one-proportion z-statistic. 'kmeRtone' is highly flexible by allowing users to also specify their target k-mer patterns and quantify the corresponding k-mer enrichment scores in the context of these patterns, allowing for a more comprehensive approach to understanding the functional implications of specific DNA sequences on a genomic scale (e.g., CT motifs upon UV radiation damage). Adib A. Abdullah, Patrick Pflughaupt, Claudia Feng, Aleksandr B. Sahakyan (2024) Bioinformatics (submitted).