Health ministry says both victims are young men and 120 people have been hospitalised since the start of the outbreak.
Spain has reported a second death in as many days from monkeypox, its health ministry has said.
The ministry gave no details on the deceased in its statement on Saturday. It reported its first death from the disease on Friday.
These are believed to be the first confirmed deaths from monkeypox since its outbreak in the European Union.
“Among the 3,750 [monkeypox] patients … 120 have been hospitalised and two have died,” the ministry said in a report, without specifying the date of the second death.
It said the victims were “two young men”, and that studies were under way to gather more epidemiological information on both cases.
The global monkeypox outbreak has seen more than 21,00 cases in nearly 80 countries since May.
There have been 75 suspected deaths in Africa, mostly in Nigeria and the Democratic Republic of the Congo, where a more lethal form of monkeypox is spreading than in the West. Brazil also reported a death linked to monkeypox on Friday.
On Friday, Spain’s health ministry reported that 4,298 people were infected with the virus, making it the leading European country for monkeypox cases. Of that total, some 3,500 cases were of men who had had sex with other men. Only 64 were women.
Health authorities are administering 5,300 vaccines that Spain received from the joint EU vaccine purchase scheme. Health workers say that is far fewer than the number needed to cover the at-risk groups.
The WHO’s European office said on Saturday that more monkeypox-related deaths can be expected.
“With the continued spread of monkeypox in Europe, we will expect to see more deaths,” Catherine Smallwood, senior emergency officer at WHO Europe, said in a statement.
The goal needs to be “interrupting transmission quickly in Europe and stopping this outbreak”, she said.
Smallwood stressed that in most cases the disease heals itself without the need for treatment.
“The usual reasons patients might require hospital care include help in managing pain, secondary infections, and in a small number of cases the need to manage life-threatening complications such as encephalitis,” she explained.
The WHO last Saturday declared the monkeypox outbreak a global health emergency.
Monkeypox has been endemic to parts of Africa for decades. Its leap to Europe and North America was linked by experts to two raves in Belgium and Spain.
It spreads mainly through skin-to-skin contact, but it can also be transmitted through bed sheets used by someone with monkeypox.
Symptoms include fever, body aches, chills, fatigue and hives. The illness has been relatively mild in many men. But people can be contagious for weeks, and the lesions can be extremely painful.