The 35th Snowdonia Marathon on Saturday sees just under 3,000 following the route around the highest peak in Wales.
Bangor University researchers are testing the endurance athletes before and after the race.
They believe differences in how the body responds to stress could hold the key to the issue.
“While general exercise boosts the immune system, endurance events cause a brief dip in our immunity levels, post-event,” explained physiologist Prof Neil Walsh.
“Our hunch is that the way in which our body’s immune defence works during stress, like a marathon, is to some extent predictable.
“It could be that hard-wired psychological characteristics can predict how our bodies respond.”
The 26.2 mile (42km) route from Llanberis in Gwynedd takes the runners up the notorious Pen-y-Pass ascent, drops into the spectacular Nant Gwynant valley to Beddgelert, before another epic climb and trail descent back into Llanberis.
This year’s event has a record number of runners registered – and had to close registration just hours after opening entries on 1 January.
It is a fact that some of those taking part will get sick after the race – while others will just shake-off the distance.
Many put it down to pre-event training but Bangor University’s research is pointing in a completely different direction.
“Recent research here suggests that we are on the right track,” said PhD student Sophie Harrison.
“It may be that physical and psychological stresses use the same pathways and so our bodies react similarly to physical stresses as they do to emotional stresses.
“We’re looking at people’s psychological types and at measures of inflammation and immunity that we can trace in saliva.
“These will show how people’s bodies are responding to the stress of the marathon.
“We want to see whether it would be possible to predict which individuals are more likely to feel poorly, above and beyond the stresses on their bodies after the race.”
The first runner over the line was Daniel Jones from Team Bath AC in a time of 02:36, according to the race’s tracking service.