The discovery dredges up past wrongs in the name of science - like the infamous Tuskegee syphilis study in this country that has long dampened minority participation in medical research - and could complicate ongoing studies overseas that depend on cooperation from some of the world's poorest countries to tackle tough-to-treat diseases.
Uncovering it gives "us all a chance to look at this and - even as we are appalled at what was done - to redouble our efforts to make sure something like this could never happen again," said Dr. Francis Collins, director of the National Institutes of Health.
The NIH-funded experiment, which ran from 1946 to 1948, was uncovered by a Wellesley College medical historian. It apparently was conducted to test if penicillin, then relatively new, could prevent some sexually transmitted infections. The study came up with no useful information and was hidden for decades.
"We are outraged that such reprehensible research could have occurred under the guise of public health," Secretary of State Hillary Rodham Clinton and Health and Human Services Secretary Kathleen Sebelius said Friday.
President Barack Obama called Guatemala's president, Alvaro Colom, later Friday to apologize. Clinton had called to apologize the night before.
"Obviously this is shocking, it's tragic, it's reprehensible," said White House press secretary Robert Gibbs. "It's tragic and the U.S. by all means apologizes to all those who were impacted."
Guatemalan Embassy official Fernando de la Cerda said his country hadn't known anything about the experiment until Clinton called to apologize Thursday night.
"We appreciate this gesture from the USA, acknowledging the mistake and apologizing," he said. "This must not affect the bilateral relationship."
Strict regulations today make clear that it is unethical to experiment on people without their consent, and require special steps for any work with such vulnerable populations as prisoners. But such regulations didn't exist in the 1940s.
The U.S. government ordered two independent investigations to uncover exactly what happened in Guatemala and to make sure current bioethics rules are adequate. They will be led by the prestigious Institute of Medicine and the Presidential Commission for the Study of Bioethical Issues.
Wellesley College historian Susan Reverby made the discovery while combing the archived records of Dr. John Cutler, a government researcher involved in the Tuskegee study that from 1932 to 1972 tracked 600 black men in Alabama who had syphilis without ever offering them treatment.
She discovered that Cutler also led the Guatemala project that went a step further: A total of 696 men and women were exposed to syphilis or in some cases gonorrhea - through jail visits by prostitutes or, when that didn't infect enough people, by deliberately inoculating them. They were offered penicillin, but it wasn't clear how many were infected and how many were successfully treated.
She reported that the U.S. had gained permission from Guatemalan officials to conduct the study, but did not inform the experimental subjects.
While secretly trying to infect people with serious diseases is abhorrent today, the Guatemalan experiment isn't the only example from what Collins on Friday called "a dark chapter in the history of medicine." Forty similar deliberate-infection studies were conducted in the United States during that period, Collins said.
"We've made some obvious moral progress" in protecting the poor and powerless, said Dr. Arthur Caplan, a University of Pennsylvania bioethicist. "The sad legacy" of past unethical experiments is that "they still shape who it is that we can get to trust medical researchers."
A continuing ethical dilemma in developing countries is what Caplan calls the "left-behind syndrome," when the people who helped test a treatment can never afford the resulting care.
"It's still ethically contentious as to how we ought to conduct, or whether we ought to conduct, certain forms of research in poor nations today," he said.
Reverby, whose work was first reported by NBC News, made the discovery last year and gave a speech about it at a medical historians' meeting in May, which a U.S. health official heard. She provided her findings to the government the next month, resulting in Friday's apology, and has posted them on her website.
The revelation of abuses by a U.S. medical research program is only the latest chapter in the United States' troubled history with the impoverished Central American nation, which has a per capita gross domestic product about half of that of the rest of Central America and the Caribbean.
The U.S. helped topple the democratically elected president Jacobo Arbenz in 1954 and backed several hardline governments during a 36-year civil war that ended in 1996 and cost 200,000 lives.
Associated Press writer Luis Alonso contributed to this report.