A three-judge panel of the federal appeals court based in Atlanta on Friday ruled the health-care overhaul law’s individual mandate is unconstitutional, in one of the largest legal challenges to the Obama administration’s signature achievement.

This is the second federal appellate court to rule on the law; the first decision, by a Cincinnati-based court, upheld the measure. It is also the most high profile ruling, responding to a challenge to the law brought by 26 states. The law’s constitutionality is likely to be ultimately decided by the U.S. Supreme Court.

In its 2-1 ruling, the panel of the Atlanta-based 11th Circuit Court of Appeals sided with a federal district court in Florida ruling that the individual mandate is not authorized under the Constitution’s Commerce clause, which allows the federal government to regulate interstate commerce.

The appellate court, did, however, overturn part of the lower court’s ruling by declaring that the rest of the law could continue to stand without the individual mandate.

“This economic mandate represents a wholly novel and potentially unbounded assertion of congressional authority: the ability to compel Americans to purchase an expensive health insurance product they have elected not to buy, and to make them re-purchase that insurance product every month for their entire lives,” the panel majority wrote in the 304-page decision.

The health-care law’s individual mandate requires the vast majority of Americans to purchase health insurance in 2014. Those who do not buy coverage will be subject to a fine.

The individual mandate quickly became the most controversial part of the Afforadable Care Act after it became law in March 2010. It has been at the heart of the 26 federal court challenges, as well as Republican attacks on the law.

The White House swiftly denounced the appeals court’s ruling against the individual mandate, saying it was confident that “it will not stand.”

“The individual responsibility provision – the main part of the law at issue in these cases – is constitutional,” Assistant to the President Stephanie Cutter wrote in a White House blog post. “Those who claim this provision exceeds Congress’ power to regulate interstate commerce are incorrect. Individuals who choose to go without health insurance are making an economic decision that affects all of us – when people without insurance obtain health care they cannot pay for, those with insurance and taxpayers are often left to pick up the tab.”

Chief Judge Joel Dubina, an appointee of President George H.W. Bush, and Circuit Judge Frank Hull, appointed by President Clinton, ruled against the individual mandate. Circuit Judge Stanley Marcus, also a Clinton appointee, dissented, accusing the court of ignoring “many years of Commerce Clause doctrine developed by the Supreme Court.”

Hull’s decisions marks the second political crossover in the appellate rulings. Judge Jeffrey Sutton of the Cincinnati-based 6th Circuit, a former clerk for Supreme Court Justice Supreme Court Anton Scalia and a Bush appointee, ruled in the law’s favor.

Having a Democratic-appointed judge rule against the law “exemplifies that this is a serious issue that is not some kind of partisan policy attack on Obama’s health care law,” says Michael Carvin, one of the attorneys who argued for the plantiffs in the case. “This is a serious constitutional challenge to an unprecedented act of Congress.”

The next appellate court ruling will likely come from the Fourth Circuit Court of Appeals, which heard oral arguments on Virginia Attorney General Ken Cuccinelli’s challenge on May 10. The panel there, comprised of three Democratic-appointees, is likely to rule by the end of September. Another case in the District of Columbia’s Third Circuit Court of Appeals has arguments scheduled for Sept. 23.

The Supreme Court is expected to take up the case in its next term, which begins this October and ends in June 2012.

This post has been updated since it was first published.