Clinical tests conducted by researchers in Britain found that clomifene citrate, best known by its brand names Clomid and Serophene, failed to improve the odds of becoming pregnant.
One of the most commonly prescribed fertility medications in the world, clomifene is designed to induce ovulation and improve egg production.
The same study of 580 women in Scotland, all of whom had experienced unexplained infertility for more than two years, also showed that so-called unstimulated intra-uterine insemination (IUI) -- artificial insemination unaccompanied by drugs to trigger egg production -- did not work any better.
The researchers did not evaluate the efficacy of the two methods used in combination, as is often done.
A quarter of all infertility cases, which affects one in seven couples, are unexplained.
"These interventions, which have been in use for many years, are unlikely to be more effective than no treatment," concludes the study, led by Siladitya Bhattacharya, a professor at the University of Aberdeen in Scotland, and published in the British Medical Journal.
"These results challenge current practice" endorsed by a national guidelines in Britain, the United States and other nations, he said in a statement.
For the trial, 580 women facing infertility were randomly divided into three groups.
One was encouraged to induce pregnancy by natural means and received no medical interventions. Another group took oral clomifene citrate, and the third were artificially inseminated with washed sperm.
The respective live birth rates for the three groups were 17, 14 and 23 percent.
To be statistically significant, they said, the difference between IUI birth and those achieved naturally would have to be much higher than the six percent reported in the trial.
In a commentary, also published in the British Medical Journal, Terek El-Toukhy and Yacoub Khalaf of Britian's National Health Service wrote: "As a direct result of the lack of evidence, many couples with unexplained infertility endure -- and even request -- expensive, potentially hazardous, and often unnecessary treatments."
Bhattacharya and his colleagues also note concerns about multiple pregnancies induced by clomefine citrate, and earlier studies pointing to a potential risk of ovarian cancer.
Ten to 20 percent of the women in the trial taking the drug complained of some combination of abdominal pain, bloating, hot flushes, nausea and headaches.