Researchers found taking HRT containing the hormones oestrogen and progestin doubled the risk of venous thrombosis for all women who took it for five years.
However, the risk was significantly higher still for older women, and those who were overweight or obese.
The research, by the University of Vermont, is published in the Journal of the American Medical Association.
However, experts have cast doubt on its relevance to the UK, where many women never take the treatment for as long as five years.
The study is based on an analysis of data from 16,608 postmenopausal women between the ages of 50 and 79.
The researchers found that venous thrombosis occurred in 167 women taking combined HRT, compared with just 76 who were taking a dummy pill.
Women aged 60 to 69 were 4.3 times more likely to develop a clot if taking combined HRT, while women in their seventies were at 7.5 times the risk.
The risk of a blood clot also increased sharply for overweight and obese women taking combined HRT. For overweight women the risk was 3.8 times higher than those of normal weight, and for obese women it was 5.6 times higher.
The researchers calculated that over a 10 year period combined HRT would be responsible for an extra 18 cases of venous thrombosis if taken by 1,000 women.
A venous thrombosis is a type of blood clot which can travel to the lungs, and potentially cause life-threatening complications.
Explain the risks
Lead researcher Dr Mary Cushman told BBC News Online the findings did not necessarily mean that combined HRT should not be offered to certain groups of women.
Rather it was important that the risks and benefits were fully explained before they started on a course of treatment.
“You have to weigh all the risks of taking it, and of not taking it,” she said.
“Combined HRT is still often the best form of treatment for a 55-year-old women who is suffering from hot flashes.”
It is thought that the hormones contained in HRT may increase the risk of a blood clot by interfering with the body’s clotting mechanism.
Most women taking HRT in the UK use a combined version. An oestrogen-only form is available, but is usually only given to women who have had a hysterectomy.
Combined HRT has previously been linked to an increased risk of breast cancer and stroke.
June Davison, of the British Heart Foundation, said previous research had also shown that HRT might increase the risk of venous thrombosis, but she said the new work highlighted the fact that overweight women were particularly vulnerable.
“This implies that maintaining a healthy weight by eating a balanced diet and regular physical activity is particularly important for these women.
“HRT has many benefits, including reducing risk of osteoporosis and relieving unpleasant symptoms of the menopause.
“Anyone concerned about taking HRT should discuss it with their doctor before making any changes to their medication.”
Karen Winterhalter, executive director of Women’s Health Concern, which advises women on hormone replacement, said: “Basically the whole study is flawed as the women were much older than the population of women who receive HRT in the UK.
“As they were an older age group they were prone to cardiovascular complications, as you would see with any older populations.”
In Britain, women go on HRT for an average of two years, between the ages of 50 and 52.
Most have the treatment to alleviate menopausal symptoms such as hot flushes.
But some take it for longer, because HRT is known to protect against osteoporosis.
However, Dr Sarah Jarvis, spokeswoman for the Royal College of GPs, said: “This confirms long-running concerns over HRT drugs.
“While they can offer short-term relief, HRT drugs should only be offered in the lowest doses and for the shortest time possible.
“The problem is often, when women stop HRT, the symptoms come back.
“My advice to patients is they should consider herbal alternatives such as black cohosh or red clover.
“One thing is clear more research needs to be done in this area.”