Researchers randomly split 187 into three groups: one drinking between three and six cups of caffeinated coffee daily, another drinking the same amount of decaffeinated coffee, and one drinking no coffee at all.
After three months they found that apolipoprotein B (ApoB), a protein associated with 'bad' LDL cholesterol and so an indicator of heart disease risk, had gone up eight per cent in the decaf group.
Levels of fat in the blood, also called non-esterified fatty acids or NEFA, also rose 18 per cent in the decaf group. There were no significant changes to either of these two in the other two groups.
"NEFA is the fuel that can drive the increase in ApoB and LDL," said lead author of the study H Robert Superko, of the Fuqua Heart Center and Piedmont-Mercer Center for Health and Learning.
"These results are very surprising and have never been reported before in coffee consumption.
"There is a real difference between caffeinated and decaffeinated coffee and, contrary to what people have thought for many years, I believe it's not caffeinated but decaffeinated coffee that might promote heart disease risk factors."
Heart health problems are one of the biggest killers in developed countries like the US, UK and France. Americans drink three cups per day on average and recent research claimed coffee was the leading source of healthy antioxidants, also found in vegetables, in the US diet.
The new study, although clearing caffeine itself, still threatens to hit coffee firms in their decaf ranges and is a blow after a study last week said coffee had no relation to increased risk of hypertension, which also causes heart disease.
Superko said the study showed thinner people may be at more risk. Those taking part considered clinically overweight, with a body mass index above 25, saw a 50 per cent rise in HDL2, or 'good' cholesterol, after drinking decaf coffee.
Their thinner counterparts, however, saw good cholesterol drop 30 per cent.
Superko said this result highlighted how complicated and particular health benefits were.
"Those who are overweight and have low levels of HDL2 but normal levels of ApoB, might consider the potential benefit of drinking decaffeinated over caffeinated coffee."
He also added that "if you only drink one cup each day, the results of our study probably have little relevance".
The debate over coffee's link to heart disease has been going on for some time, though the American Heart Association says one or two cups per day does not seem to be harmful.