OBJECTIVE: To estimate long term trends in estrogen-progestin prevalence for the U.S. female population by year and age. METHODS: We integrated data on oral estrogen-progestin use from the National Health and Nutrition Examination Survey 1999-2010 with data from the National Prescription Audit 1970-2003. Distributions of estrogen-progestin by age from the National Health and Nutrition Examination Survey were applied to the prescription data, and calibration and interpolation procedures were used to generate estrogen-progestin prevalence estimates by single year of age and single calendar year for 1970-2010. RESULTS: Estimated prevalence of oral estrogen-progestin was below 0.5% in the 1970s, began to rise in the early 1980s, and almost tripled between 1990 and the late 1990s. The age-adjusted prevalence for women aged 45-64 years peaked at 13.5% in 1999 with highest use among 57-year-old women (23.2%). Prevalence of estrogen-progestin use declined dramatically in the early 2000s with only 2.7% of women aged 45-64 years using estrogen-progestin in 2010, which is comparable to prevalence levels in the mid-1980s. CONCLUSION: The dramatic rise and fall of estrogen-progestin use over the past 40 years provides an illuminating case study of prescription practices before, during, and after the development of evidence regarding benefits and harms.