Antibiotic "stalwarts" like penicillin and amoxicillin do not work in a significant number of cases, US research has suggested.
The researchers call for a move away from 'traditional' antibiotics
University of Rochester experts looked at data on almost 11,500 children with a common throat infection.
A quarter of those given penicillin and 18% of those on amoxicillin needed further treatment within weeks.
Scientists told a Washington conference that newer antibiotics should be used more, but a UK expert urged caution.
The data, from an analysis of 47 studies from the past 35 years looking at the effectiveness of various drugs on treating strep throat in children, was presented to the Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington.
The researchers also found that, of those given older-generation cephalosporin antibiotics, 14% had to return for more treatment, while just 7% prescribed newer versions like cefpodoxime and cefdinir, given for just four or five days, had to go back to the doctor.
The results back up previous work by the team, published in Pediatrics last year, which reported the waning effectiveness of penicillin and amoxicillin.
The scientists suggest other bacteria which can be present in the throat can hamper the effectiveness of the drugs.
This happens because many bacteria produce enzymes called beta-lactamase that can inactivate penicillin and amoxicillin.
Strep does not - but it is possible the other bacteria which do are present in the throat and can inactivate a drug before it has a chance to work
Professor of microbiology and immunology Michael Pichichero, who led the research team, said: "Most doctors are shocked to learn of the high failure rates of the older medications.
"The treatment paradigm [model] for treating strep sore throats has been changing slowly, and endorsing the use of cephalosporins as a first-line treatment is something that needs to be seriously considered."
He added that most drugs will fail to be effective some of the time, but doctors would view a drug that fails in one out of four patients as unacceptable.
Dr Robert George, director of the Respiratory and Systemic Infection Laboratory and a consultant medical microbiologist for the Health Protection Agency, said: "The World Health Organisation continues to recommend penicillin as the first line of treatment for strep throat and the Health Protection Agency guidance is in accordance with this."
He added: "Although prescribing cephalosporins might reduce a strep throat infection in a shorter time period, the effects of using a more potent antibiotic must be considered."
Dr George warned using the antibiotics more regularly for strep throat could increase the amount of resistance to the medication, potentially reducing its effectiveness against the broad range of bacteria it can target.