Some people with high levels of supposedly "good" cholesterol are at much greater risk of heart disease, a study suggests.
A bloodstream tussle takes place between "bad" cholesterol dumping fatty material in the arteries and good cholesterol taking it away.
But a Cambridge University study in the journal Science showed more good cholesterol was not always better.
It is thought the findings may help find new ways to protect the heart.
Eating olive oil, fish and nuts raises levels of high-density lipoprotein (HDL) — which is more commonly known as good cholesterol.
It is one of the things doctors test for when predicting your risk of a heart attack.
However, repeated trials that raise HDL with drugs have flopped, leading doctors to think something else is going on.
Rare mutation
Some insight has come from studying rare mutations that leave people with high levels of good cholesterol.
Trials showed people with a mutation in a gene called SCARB1, which affects one-in-1,700 people, had very high levels of good cholesterol.
But they also had an 80% increased risk of heart disease — that is roughly the same increased risk as for smoking.
Further experiments showed the mutation was preventing HDL from dumping the fat it had collected in the liver for processing.
Prof Adam Butterworth, one of the researchers from the University of Cambridge, told the BBC News website: "This is significant because we had always believed that good cholesterol is associated with a lower risk of heart disease.
"This is one of the first studies to show that some people that have high levels of 'good' cholesterol actually have a higher risk of heart disease so it challenges our conventional wisdom about whether 'good' cholesterol is protecting people from heart disease or not."
There have been huge efforts put into drugs to raise HDL in the hope they have the same impact as statins, which lower the bad cholesterol.
Prof Butterworth warned that drugs aimed simply at "trying to raise HDL may not be that useful".
He said the size of different HDL particles or how good they are at transporting may be more important than the overall levels.
And that may be a more productive avenue of research.
While the researchers have questioned the importance of boosting levels of HDL cholesterol, they insist it still remains a valuable tool for predicting the risk of a heart attack.
Although fellow researcher Dr Daniel Rader, from the University of Pennsylvania, added: "Eventually we may want to perform genetic testing in persons with high HDL to make sure they don't have mutations, like this one, that raise HDL but don't protect against, or may even increase, risk for heart disease."
Dr Tim Chico, a consultant cardiologist based at the University of Sheffield, said: "This important study adds to other results showing it isn't as simple as good and bad.
"It is worth noting that exercise both increases HDL and reduces the risk of heart disease.
"These results suggest that the beneficial effect of exercise is probably not caused by higher HDL levels, although more research is needed to fully understand the complex relationship between HDL and risk of heart disease."
Prof Peter Weissberg, the medical director at the British Heart Foundation, said: "This is an important study that sheds light on one of the major puzzles relating to cholesterol and heart disease.
"These new findings suggest that the way in which HDL is handled by the body is more important in determining risk of a heart attack than the levels of HDL in the blood.
"Only by understanding the underlying biology that links HDL-C with heart attacks can we develop new treatments to prevent them."