Abstract Human endogenous retroviruses (HERV) have been implicated in a variety of diseases including cancers. Recent research implicates HERVs in epigenetic gene regulation. Here we utilize a recently developed bioinformatics tool for identifying HERV expression at the locus-specific level to identify differential expression of HERVs in matched tumor-normal RNA-sequencing (RNA-seq) data from The Cancer Genome Atlas. Data from 52 prostate cancer, 111 breast cancer, and 24 colon cancer cases were analyzed. Locus-specific analysis identified active HERV elements and differentially expressed HERVs in prostate cancer, breast cancer, and colon cancer. In addition, differentially expressed host genes were identified across prostate, breast, and colon cancer datasets, respectively, including several involved in demethylation and antiviral response pathways, supporting previous findings regarding the pathogenic mechanisms of HERVs. A majority of differentially expressed HERVs intersected protein coding genes or lncRNAs in each dataset, and a subset of differentially expressed HERVs intersected differentially expressed genes in prostate, breast, and colon cancers, providing evidence towards regulatory function. Finally, patterns in HERV expression were identified in multiple cancer types, with 155 HERVs differentially expressed in all three cancer types. This analysis extends previous results identifying HERV transcription in cancer RNA-seq datasets to a locus-specific level, and in doing so provides a foundation for future studies investigating the functional role of HERV in cancers and identifies a number of novel targets for cancer biomarkers and immunotherapy. Significance: Expressed human endogenous retroviruses are mapped at locus-specific resolution and linked to specific pathways to identify potential biomarkers and therapeutic targets in prostate, breast, and colon cancers.