OBJECTIVES: The novel progestin drospirenone (DRSP) has antimineralocorticoid properties with potentially beneficial as well as unfavorable effects on cardiovascular outcomes compared to other progestins. A patient based AS study was set up to compare incidence rates of serious adverse events - in particular cardiovascular outcomes - in users of oral continuous combined preparations. METHODS: Prospective, controlled cohort study (2002-2011) with three arms: women using 1) DRSP/estradiol, 2) other oral continuous-combined HRT (occHRT), and 3) all other oral HRTs. The study population included women aged 40 or older in seven European countries starting or switching to an oral HRT at time of inclusion in the study. Outcomes were collected from the patients and validated by the treating physicians. A multifaceted 4-level follow-up procedure was to ensure low loss to follow-up rates. The analysis is based on Cox regression models comparing the cohorts. RESULTS: A total of 30,597 users of oral HRT preparations - reflecting more than 101,000 WY of observation - were recruited by 1,052 centers. Incidence rates of DRSP/estradiol and low-dose occHRT for venous thromboembolic events were 17.5 (95% CI: 11.2-26.0) and 18.2 (95% CI: 11.9-26.6) per 10,000 WY, respectively. The respective incidence rates for arterial thromboembolism were 10.9 (95% CI: 6.1-18.0) and 29.8 (95% CI: 24.1-36.4 ) per 10,000 WY with a hazard ratio adjusted for age, BMI, hypertension, region, family history of fatal ATE, diabetes, user status of 0.5 (95%CI: 0.3-0.8) for DRSP/estradiol vs. other occHRT. CONCLUSIONS: Results indicate a good safety profile with respect to cardiovascular risk for DRSP/estradiol. Serious cardiovascular events occur less frequently in DRSP/estradiol users compared to users of other continuous-combined HRT. This specificAS approach proved to be a successful approach with high long term follow-up success and high validity of safety results.