This research work deals with chlorite-vermiculite mixed-layer stability under hydrothermal and metamorphic conditions. We used as a case study a clayey flysch unit cropping out in an active geothermal area near to a Recent volcano (Mt. Amiata) in central Italy. The geothermal gradient is higher than the world average and temperatures over 100°C can occur at less than 1 km depth. The mineralogical data, obtained from X-Ray Power Diffraction (XRPD) analysis of clay samples from the same geologic unit, show that the primary anchimetamorphic mineral assemblage (illite, chlorite, illite-smectite mixed layers) is accompanied by secondary phases, such as chlorite-vermiculite mixed-layers and calcite. Reactive flow modelling was used to outline a realistic water-rock (W/R) interaction process able to generate the new minerals. In the numerical simulation, the pristine shale was made to react with a local thermal spring, at an estimated but realistic carbonate reservoir temperature. The simulation predicts that, at a temperature of 120°C, clinochlore dissolves and vermiculite crystallizes, a good proxy of the chlorite-vermiculite crystallization process. Under low water/rock conditions the proportions of the clay minerals (illite, chlorite, smectite and vermiculite) are comparable with the analytical results. The simulation also shows that temperatures higher than 120°C enhance the vermiculite formation. We conclude that the chlorite-vermiculite mixed-layers formed in the recent past due to the upflow of thermal water which permeated the flysch unit. This result indicates that the alteration of the clayey cap-rocks of geothermal reservoirs is enhanced by the interaction with geothermal fluids, and can be used as a prospecting tool.