The study looked at the risk of pulmonary embolism -- blood clots in the lungs that typically arise from a vein constriction in the legs -- among 69,950 female nurses over an 18-year period.
Previous research has highlighted a number of factors for this condition, including age, immobility on long-haul flights, obesity, smoking and hypertension.
The new research suggests that a sedentary lifestyle can be added to the list.
Over the 18-year study period, there were 268 cases of pulmonary embolism.
The risk more than doubled in women who spent more than 41 hours a week sitting down outside the workplace compared to those who were seated for less than 10 hours per week.
Results held even after age, weight and tobacco consumption were taken into account.
The study, published online by the British Medical Journal (BMJ), is led by Christopher Kabrhel at Massachusetts General Hospital.
Researchers called for further work to see if the results also applied to men, and to people not of European origin.
They also pointed out that the mean age of the women studied was 55, leaving open the question of whether younger women would be subject to the same risks.