High-density lipoprotein (HDL), or "good" cholesterol, normally protects against heart and artery disease by helping to keep blood vessels clear.
Yet trials have failed to show that raising HDL levels in patients leads to signficant improvements in cardiovascular health.
Story continues below the slideshow:
The new research suggests that one reason for this is HDL's change from hero to villain in patients with artherosclerosis, or hardening of the arteries.
A key protein in HDL, apoA1, that allows the molecule to remove "bad" cholesterol from artery walls becomes oxidised and joins forces with its harmful cousin.
Blood tests conducted on 627 patients in the US showed that higher levels of the dysfunctional HDL raised the risk of heart and artery disease.
"Identifying the structure of dysfunctional apoA1 and the process by which it becomes disease-promoting instead of disease-preventing is the first step in creating new tests and treatments for cardiovascular disease," said lead researcher Dr Stanley Hazen, from the Cleveland Clinic.
The research is reported in the latest edition of the journal Nature Medicine.