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The winery was founded in 1840 by Clemente Santi (1795-1885) two kilometres south of the town of Montalcino in the Italian region of Tuscany. The name "Il Greppo" comes from the steep slopes on the property. The founder's daughter Caterina Santi and Jacopo Biondi continued to expand the winery. Their son Ferruccio Biondi-Santi (1848-1916) continued the efforts already begun by his grandfather to select high-quality Sangiovese vines. He finally created the Sangiovese variety Brunello and in 1888 produced a dry red wine in the style of Barolo for the first time, which later became famous as DOCG red wine Brunello di Montalcino

Until after the Second World War, this was exclusively produced commercially by Biondi-Santi. Ferruccio introduced an extremely elaborate cellar technique for the Riserva version, which was consistently continued by his son Tancredi. The outstanding Brunello Riserva vintages from vines at least 25 years old were produced with long fermentation and five to six years of barrel ageing. For the first 57 years, they were only available in 1888, 1891, 1925 and 1945. The famous wine author Burton Anderson was inspired to write about wine during a visit to the winery. He published the book: "Biondi Santi: the family that created Brunello di Montalcino" in 1988.

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