The team tracked the health of nearly 800 villagers from the Chianti region of Italy to see if their local tipple had any discernable impact.
They found no proof that the wine ingredient resveratrol stops heart disease or prolongs life.
Experts say more research is needed to get a definitive answer.
The British Heart Foundation is carrying out its own resveratrol study.
Many studies have sought to explain why there is a low incidence of heart disease in France, despite many of its inhabitants eating a high-fat diet.
Some put it down to moderate drinking of red wine.
Studies have shown that consumption of red wine, dark chocolate and berries reduces inflammation, leading researchers to speculate that their common ingredient, resveratrol, explains why.
But Prof Richard Semba, of the Johns Hopkins University School of Medicine, and colleagues found no evidence for this.
They chose two small towns in Tuscany as their test ground, and 783 elderly people who were living there agreed to take part in their investigation.
The volunteers gave details about their daily diets as well as urine samples for measurement of their resveratrol intake.
During the nine years of the study, 268 of the men and women died, 174 developed heart disease and 34 got cancer.
But urinary resveratrol was not linked with death risk, heart disease risk or cancer risk.
Nor was it associated with any markers of inflammation in the blood, the researchers report in JAMA Internal Medicine.
Prof Semba said: "The thinking was that certain foods are good for you because they contain resveratrol. We didn't find that at all.
"The story of resveratrol turns out to be another case where you get a lot of hype about health benefits that doesn't stand the test of time."
He says any benefits of drinking wine or eating dark chocolate or berries, if they are there, must come from other shared ingredients. And it's not clear how much you might need to eat or drink.
"These are complex foods, and all we really know from our study is that the benefits are probably not due to resveratrol."
Maureen Talbot, senior cardiac nurse at the British Heart Foundation, said: "The results of this study, while interesting, will not change the dietary advice we provide. People should continue to eat plenty of fruit, veg and wholegrains.
"We recognise the need to learn more about the action of resveratrol though, so are funding research into its reported disease-combating properties and how it affects the heart and circulatory system.
"This research is vital as it could form the basis of future medicines."

Last week, Marriott appeared to have outbid Anbang with a $13.6bn offer that gained support from Starwood's board.
In a statement, Starwood's board said the new offer was likely to lead to a "superior proposal".
The board, though, has not changed its recommendation in favour of a merger with Marriott.
Starwood owns several hotel brands, including Sheraton, Westin and St Regis.
Under the terms of its agreement with Marriott, Starwood's board can discuss and provide information to bidders that make superior bids.
But under its latest merger agreement with Marriott, Starwood would have to pay a breakup fee to Marriott of $450m if it decided to accept another offer.
Anbang, whose consortium includes private equity firms JC Flowers & Co and Primavera Capital, has been making a push into the US market over the last several year.
It bought the Waldorf Astoria hotel in New York in 2014.
Starwood shares rose 2% on Monday to $83.75 on the higher Anbang offer.
Red wine may not be as good for you as hoped, say scientists who have studied the drink's ingredient that is purported to confer good health.
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Chinese insurance firm Anbang has raised its offer for Starwood Hotels to $14bn (£9.8bn), extending a bidding war with Marriott for the group.