Buso della Rana and Buso della Pisatela are two karstic caves located in north-east Italy. They are part of the same karst system and are developed in the Castelgomberto calcarenitic marine sediments, which were deposited in a shallow Caribbean-type sea during the Eocene. The Buso della Rana-Pisatela system developed mostly at the contact between the Castelgomberto calcarenite and underlying volcanic rocks. The system of caves is ~37 km long and has only three entrances, two of which are semi-artificial. The overlying karst plateau is not directly connected to the Buso della Rana-Pisatela system and, with the exception of one deep abyss, exhibits a rather poorly developed karst. This is unexpected considering the presence at depth of such a large and long cave. Gypsum (CaSO4·2H2O) has locally been observed on the walls of the Buso della Pisatela cave. Energy dispersive X-ray spectroscopy (EDS), performed with a scanning electron microscope (SEM), reveals the presence of sulfur-bearing minerals within the host rock. Gypsum was formed by oxidation of these minerals as indicated by negative δ34S values. The oxidation of sulfide minerals forms a sulfuric-acid solution that dissolves the Castelgomberto calcarenite and, once it is oversaturated in calcium, precipitates as gypsum. The lack of well-developed karst on top of the plateau and the analyses suggest that the formation mechanisms for the Buso della Rana-Pisatela system differ from classical epigenic speleogenesis. The “pyrite-effect” has been recognized in other caves and described in literature. In our case pyrite is responsible of two hypo-speleogenetic processes: i) the dissolution of a portion of the host rock and ii) the enlargement of the karst voids as a consequence of the haloclastic effect.