It appeared to be the first time health workers have been killed by rebels in this outbreak, which is taking place in what has been compared to a war zone.
Multiple rebel groups are active in Congo's far north east.
Mai Mai rebels surged from the forest and opened fire on the unarmed agents with the army's rapid intervention medical unit at an entrance to Butembo city, the health ministry said.
The daytime attack appeared premeditated, with civilians present left unharmed, the statement said.
The medical agents had been placed in "dangerous zones" to assist national border health officials.
Confirmed Ebola cases have now reached 200, including 117 deaths.
Aid groups have expressed alarm after the insecurity and sometimes hostile community resistance led the rate of new cases to more than double this month.
Health workers in this outbreak, declared on 1 August, have described hearing gunshots daily, operating under the armed escort of UN peacekeepers or Congolese security forces and having to end work by sunset to lower the risk of attack.
The health ministry has reported "numerous aggressions" against health workers. Early this month, two Red Cross volunteers were severely injured in a confrontation with wary community members in a region traumatised by decades of fighting and facing an Ebola outbreak for the first time.
A deadly rebel attack against civilians in Beni late last month forced the suspension of Ebola containment efforts for days and the effects are still seen.
Many of the new confirmed cases this month, including six reported on Saturday, have been in Beni, where most of the Ebola work is based.
"Health agents are not a target for armed groups," health minister Oly Ilunga said.
"Our agents will continue to go into the field each day to fulfil the mission entrusted to them. They are true heroes and we will continue to take all necessary measures so that they can do their job safely."
On Wednesday, the World Health Organisation said it was "deeply concerned" by the outbreak but that it does not yet warrant being declared a global emergency.
An outbreak must be "an extraordinary event" that might cross borders, requiring a co-ordinated response.
Confirmed cases have been found near the heavily-travelled border with Uganda.
In the latest sign of the rumours that pose another serious challenge to containing the deadly virus, the health ministry said 22 youths in Butembo dug up the body of an Ebola victim and opened the body bag, "wanting to verify that no organs had been taken from the body by health workers".
They ended up touching the highly infectious bodily fluids, the ministry said.
"The next day, they agreed to be vaccinated," it added, joining the more than 20,000 people who have received vaccinations so far.
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