Calcific aortic valve disease is common in older adults and a major cause of aortic stenosis. Despite its clinical impact, there are still no effective drugs that slow disease progression, and treatment largely relies on surgical or transcatheter valve replacement once stenosis becomes severe and symptomatic. Beyond established roles for inflammation and tissue remodeling, recent evidence suggests that chemical modifications of RNA may influence how valve cells shift toward fibro-calcific states. In this study, we compared human valvular interstitial cells isolated from non-calcified valves and from fibro-calcific stenotic valves, profiling RNA modifications using direct RNA sequencing. The resulting epitranscriptomic patterns clearly separated control from diseased cells and revealed an overall increase in detected modification sites in disease, alongside site-specific gains and losses across selected transcripts. Network-based prioritization highlighted genes linked to extracellular matrix remodeling and inflammatory signaling, pointing to stress-responsive regulators as notable candidates. Overall, these findings support the idea that disease-associated RNA modification remodeling accompanies, and may help shape, key cellular programs in calcific valve disease, providing a focused set of targets for future functional validation and potential non-surgical therapeutic exploration.