José María Postigo, known as Chema to his friends, died on Monday aged 56, after a short illness. He left behind his widow and 15 of their children.
He was admitted to the hospital two weeks ago and diagnosed with liver cancer after losing 11 kg in just six weeks.
His entire family were at the bedside.
The story of the couple is extraordinary. José María, who was one of 16 children, met Rosa Pich, who was the seventh child of 14. They went on to have 18 children of their own.
José and Rosa's first child was born with a severe heart defect and despite the fact that doctors only gave her three years to live, Carmen lived to 22, dying in 2012 after completing her Masters degree.
The couple's next two children died of the same heart condition; one aged only ten days and one 18 months.
After the health issues of their first three children, doctors advised José and Rosa not to have any more - but amazingly they went on to have a further 15.
The couple are members of Opus Dei, an organization within the Catholic Church, and founded a charity to help children with heart conditions. Rosa has written a book about her experience as a mother of Spain's largest family: "How to be happy with 1,2,3… children".
The family has appeared on television programmes around the world, from a BBC report "The biggest family in the world" to South Korean news and dozens of Spanish documentary shows.
Rosa described how the monthly family supermarket trip involved filling four shopping trolleys and that the average grocery list included 1.300 biscuits, 249 litres of milk, 25 kilos of potatoes and 25 kilos de carne.
The family gets through 96 toilet rolls each month and has two sittings for breakfast and dinner.
In December 2015, the family were recognized for having the most school-age children in Spain "and possibly Europe". They were chosen by the European Large Families Confederation (ELFAC) as Europe's Large Family of the Year.
On the occasion, they were awarded a cheque for €5,000 which they donated to help other big families.
Thousands have paid tribute to Chema, who was loved and leaves behind an impressive legacy.