Five previous reported deaths were all in African nations.
The Spanish Ministry of Health confirmed the fatality as it revealed 4,298 cases have so far been notified.
Of the 3,750 patients it had information on, 120 had been hospitalised – accounting for 3.2 per cent.
The agency declined to give details about the deceased person or when they passed away.
Only 64 of the confirmed cases in Spain have involved women.
Earlier this month when the number of confirmed cases stood at just over 3,000 in Spain, it was identified as the monkeypox world leader.
The earliest 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 Organisation last Saturday declared the outbreak which has rapidly spread to 75 countries a global health emergency, its highest level of alert.
This week, the NHS announced it was stepping up its vaccination programme against monkeypox in London as more supplies of a jab become available.
On Tuesday, the UK Health Security Agency said it had procured 100,000 more 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 monkeypox, the majority of cases in the UK continue to be in gay, bisexual and other men who have sex with men.
Vaccination experts have recommended that gay and bisexual men at higher risk of exposure to monkeypox should be offered the smallpox vaccine Imvanex.
Dr Meera Chand, director of clinical and emerging infections at UKHSA, said the WHO declaration of an emergency “recognises the rapid spread of the virus globally, 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 Organisation, and to share our clinical and epidemiological findings and public health approach to the outbreak.
“The risk to the UK remains the same. If you have monkeypox symptoms, take a break from attending events or sex until you’ve called 111 or a sexual health service and been assessed by a clinician.
“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 you have skin-to-skin or sexual contact with someone new.”