Statins reduce levels of low-density lipoprotein, the "bad" form of cholesterol linked to heart disease. But up to 40% of those taking them are resistant to their effects, according to the new research.
The reason may be a fat-generated protein called resistin, which not only causes high levels of LDL, but also counteracts the beneficial effects of statins.
Lead researcher Dr Shirya Rashid, from McMaster University in Canada, said: "The bigger implication of our results is that high blood resistin levels may be the cause of the inability of statins to lower patients' LDL cholesterol levels."
The discovery of resistin's role in raising cholesterol could lead to new therapeutic drugs that target the protein, she believes.
Dr Rashid's team showed resistin increases the production of LDL in human liver cells, and reduced the liver's ability to clear "bad" cholesterol out of the body.
The protein accelerated the accumulation of LDL in arteries, leading to a narrowing of the blood vessels and an increased risk of heart disease.
Results from research were presented at the Canadian Cardiovascular Congress in Toronto.
Dr Beth Abramson, from the Heart and Stroke Foundation of Canada, said: "The possibilities for improved therapy for the causes of cardiovascular disease are very important.
"Fortunately, we know a great deal about heart disease prevention."
She urged people to monitor their weight and waist size, eat low-fat food, and be physically active.
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