The magmatic system feeding the last eruption of the volcano La Fossa, Vulcano Island, Italy was studied. The petrogenetic mechanisms controlling the differentiation of erupted rocks were investigated through petrography, mineral chemistry, major, trace and rare earth element and Sr, Nd and Pb isotopic geochemistry. In addition, melt inclusion and fluid inclusion data were collected on both juvenile material and xenolithic partially melted metamorphic clasts to quantify the P-T conditions of the magma chamber feeding the eruption. A regular and continuous chemical zoning has been highlighted: rhyolites are the first erupted products, followed by trachytes and latites, whereas rhyolitic compositions were also found in the upper part of the sequence. The chemical and isotopic composition of the rhyolites indicates that they originated by fractional crystallization from latitic magmas plus the assimilation of crustal material; the trachytes represent hybrid magmas resulting from the mixing of latites and rhyolites, contaminated in the shallow magmatic system. The erupted products, primarily compositionally zoned from latites to rhyolites, are heterogeneous due to syn-eruptive mingling. The occurrence of magmacrust interaction processes, evidenced by isotopic variations (87Sr/86Sr=0.70474±3 to 0.70511±3; 143Nd/144Nd=0.512550±6 to 0.512614±8; 206Pb/204Pb=19.318–19.489; 207Pb/204Pb=15.642–15.782; 208Pb/204Pb=39.175–39.613), is confirmed by the presence of partially melted metamorphic xenoliths, with 87Sr/86Sr=0.71633±6 to 0.72505±2 and 143Nd/144Nd=0.51229±7, in rhyolites and trachytes. AFC calculations indicate a few percentage contribution of crustal material to the differentiating magmas. Thermometric measurements on melt inclusions indicate that the crystallization temperatures of the latites and trachytes were in the range of 1050–1100° C, whereas the temperature of the rhyolites appears to have been around 1000°C at the time of the eruption. Compositional data on melt inclusions reveal that the magmas involved in the eruption contained about 1–1.5 wt.% dissolved H2O in pre-eruptive conditions. Secondary fluid inclusions found in metamorphic xenoliths give low equilibration pressure data (30–60 MPa), giving the location of the higher portions of the chamber at around 1500–2000 m of depth.