Tamoxifen's protection lasts at least two decades and, while women are taking it, it cuts their risk of developing breast cancer by around 30%, according to scientists.
After 20 years, the estimated risk of developing breast cancer was 8% in women treated with tamoxifen for five years compared with 12% for women given an inactive placebo pill.
Professor Jack Cuzick, from Queen Mary, University of London, who led the Ibis-I (International Breast Cancer Intervention Study) trial, said: "Tamoxifen is a well-established and effective treatment for certain breast cancers, but we now have evidence of its very long-term preventive benefits.
"The preventive effect of tamoxifen is highly significant, with a reduction in breast cancer rates of around a third and this impact has remained strong and unabated for 20 years.
"We hope these results will stimulate more women, particularly younger women, to consider treatment options for breast cancer prevention if they have a family history of the disease or other major risk factors."
A total of 7,154 pre and post-menopausal women aged 35 to 70 took part in the trial, all of whom were considered at high risk of breast cancer.
Most had a family history of the disease.
The women were randomly allocated either 20 milligram daily doses of tamoxifen or a placebo for a total of five years.
After completing the treatment course, their health was monitored for up to 22 years.
The findings, published in The Lancet Oncology journal, showed that women on hormone replacement therapy (HRT) while taking tamoxifen benefited significantly less than those who did not boost their oestrogen levels.
Tamoxifen works by blocking molecular receptors on cancer cells that are stimulated by oestrogen.
It is only effective against hormone-sensitive breast cancer.
Rates of endometrial, or womb, cancer - a known but uncommon side effect of taking the drug - were 3.8 times greater among women in the tamoxifen group during the five years of treatment.
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But this increased risk was not seen over the complete follow-up period.
Despite helping to prevent breast cancer, there was no evidence that tamoxifen reduced deaths caused by the disease.
In total, 31 women given tamoxifen died from breast cancer compared with 26 of those assigned to the placebo treatment.
In addition, five women receiving tamoxifen died from womb cancer compared with none in the placebo group.
Deaths from other causes were very similar in both groups.
Prof Cuzick added: "Despite a clear and continuing reduction in breast cancer rates, this has not yet resulted in a reduction in breast cancer deaths.
"However, the number of deaths is still small compared with the number of breast cancer cases - which is 10 times higher.
"We will need to continue monitoring these women for a further decade to get a clearer picture of the impact of tamoxifen on death rates.
"Some of the side effects of tamoxifen are also cause for concern and need continued monitoring, specifically the increased occurrence of endometrial cancer."
He said that for most post-menopausal women, another type of drug called an aromatase inhibitor may be a better choice since it was more effective than tamoxifen and had fewer side effects.
The NHS cost effectiveness watchdog the National Institute for Health and Care Excellence (Nice) was now considering calls to include the aromatase inhibitor anastrozole in its guidelines for breast cancer prevention.
For younger pre-menopausal high risk women, tamoxifen remained "the only drug of choice for breast cancer prevention", Prof Cuzick said.
Dr Julie Sharp, head of health information at the charity Cancer Research UK, which funded the study, said: "The landmark Ibis trials show the value of chemoprevention for women at high risk of breast cancer and highlight just how important these large and long-term studies are.
"This follow up of Ibis-I confirms that tamoxifen has a long-lasting effect in reducing cases of breast cancer in women at high risk of the disease.
"All these drugs have side effects so it's important that women at high risk of breast cancer talk through their choices with their doctor to work out the best option for them."
The findings were also presented at the San Antonio Breast Cancer Symposium taking place in Texas.
Katherine Woods, senior research communications manager at Breast Cancer Campaign, said: "The best weapon in overcoming breast cancer is the ability to stop it occurring in the first place and today's findings add valuable knowledge to our understanding of the long-term preventive benefits of tamoxifen.
"It's particularly interesting to see the results suggest that tamoxifen is most effective at preventing oestrogen receptor-positive breast cancers, the most common type of the disease.
"This trial has advanced our understanding in this area, however, there is still so much we don't know about how chemoprevention drugs work - for instance, we need to know far more about which women are likely to benefit from these treatments, which can have harsh and serious side effects."