The study, published Wednesday in the Journal of American Medecine (JAMA), found a link between regular consumption of fizzy colas, including diet varieties, and increased risk of hypertension.
Researchers from various institutions, including Harvard School of Public Health, surveyed 155,594 women, with no recorded hypertension, over 12 years.
They had intended to examine links between caffeine drinks and hypertension generally, but said that, over the long-term, they found "strong evidence to refute speculation that coffee consumption is associated with an increased risk in women".
Yet, the good news for the beverage industry was quickly dashed by new fears over fizzy colas.
More than 30,000 of the women were diagnosed with hypertension at the end of the 12 years. "We speculate that it is not caffeine but perhaps some other compound contained in soda-type soft drinks that may be responsible for the increased risk in hypertension," said the researchers, warning this could have a "considerable impact on public health".
Hypertension is recognised as a major risk factor for coronary heart disease, stroke and congestive heart failure.
Around 50m Americans, almost one sixth of the US population, are thought to have hypertension and the number is increasing, according to JAMA.
The study lands a fresh blow on soft drink makers, who have already struggled to hold up sales for carbonated ranges this year. Both Pepsi and Coca-Cola have recorded consistent fizzy cola sales declines in the US as health-conscious consumers move to non-carbonated juice, water and sports drinks.
Diet sodas have fared a little better than their regular counterparts, but these are now also threatened by the study's findings.
The American Beverage Association (ABA), representing soft drink heavyweights Coca-Cola and PepsiCo among others, unsurprisingly advised caution.
"The authors themselves acknowledge the limitations of their study and state that it is too soon to draw any conclusions regarding soft drinks."
The ABA said other factors were also associated with hypertension, such as lifestyle, stress and certain other health conditions. Further study may help to determine the importance of soft drinks in relation to these.
The researchers also called for more research on how fizzy colas may increase a risk of hypertension. "Even small reductions in the prevalence of hypertension could have a large public health and financial impact."