People think that Europe‘s first fatality from the disease and only the second outside Africa in the current outbreak.
Five previously reported deaths were all in African countries.
The Spanish Ministry of Health confirmed the fatal accident as 4,298 cases have been reported so far.
Of the 3,750 patients it had information about, 120 had been hospitalized, accounting for 3.2 percent.
The agency declined to provide details about the person who died or when they died.
Only 64 of the confirmed cases in Spain involved women.
Earlier this month, when the number of confirmed cases in Spain was just over 3,000, it was identified as the world leader in monkey pox.
The first cases in May were linked to a gay sauna in Madrid and a Pride festival in Gran Canaria.
Earlier on Friday, Brazil reported the first monkeypox-related death outside the African continent in the current wave of the disease.
The World Health Organization on Saturday declared the outbreak that has spread rapidly to 75 countries as a global health emergency, the highest alert level.
This week the NHS announced it was ramping up its monkey pox vaccination program in London as more supplies of a shot became available.
On Tuesday, the UK Health Security Agency said it had obtained 100,000 additional doses of an effective vaccine.
As of July 21, there were 2,208 confirmed cases in the UK, of which 2,115 were in England.
While anyone can get monkey pox, most cases in the UK are still in gay, bisexual and other men who have sex with men.
Vaccination experts have recommended that gay and bisexual men at higher risk of monkeypox exposure be offered the smallpox vaccine Imvanex.
dr. Meera Chand, director of clinical and emerging infections at UKHSA, said the WHO emergency statement “recognizes the rapid spread of the virus worldwide, and the need for global coordination to investigate and prevent further transmission”.
dr. Chand added: “The UK continues to work closely with the World Health Organization and share our clinical and epidemiological findings and public health approach to the outbreak.
“The risk to the UK remains the same. If you have symptoms of monkeypox, take a break from attending events or having sex until you have called 111 or a sexual health service and have been assessed by a doctor.
“It can take up to three weeks for symptoms to appear after being in contact with someone with monkeypox, so stay alert for symptoms after having skin-to-skin or sexual contact with someone new.”