The male victims - the highest death toll since the race was first launched - were among around 50,000 people running the 13-mile course from Newcastle, across the famous Tyne bridge to Gateshead and on to South Shields in a bid to raise up to £10 million for good causes.
Ambulance officials said the only factor they could put the deaths down to was the “warm weather and sunshine” as medical staff reported a higher number of casualties than in previous years.
A Northumbria Police spokesman said: “I can confirm four male participants in the race have died, which is more than the usual one or two - but every year more people are taking part.”
North East Ambulance Service, the British Red Cross and St John Ambulance all provided medical assistance for the event.
A North East Ambulance Service spokesman said: “We all dealt with a higher number of cases this year compared to last year’s run. We don’t have any specific figures yet, but there was a particularly busy two-hour period around lunchtime.
“The only thing we can put this down to is the warm conditions. To have four fatalities in the one run is unusual.”
One of the runners, Paul Bouch, 25, said: “After about 10 miles the ambulances were everywhere and some of the people looked in a bad way. But it was difficult to get the ambulances to the roadside because it’s just so packed with people.”