Initiating and conducting large controlled clinical trials within an Health Maintenance Organization (HMO) is complex and challenging but also provides a unique opportunity to generate genuine independent research. The authors describe their experience in executing a large scale primary care based clinical trial, without any commercial funding or support. It relied on the organizational and information technology capabilities of the HMO and it's strict quality routines of medical care. Various options were explored for swift and effective recruitment of individuals for the study. Attentiveness to the needs and comments of the primary care teams proved to be important in creating effective collaboration. Methods were developed for the retrieval of pertinent clinical data, including hospitalization discharge summaries, without the need of collaboration from the primary clinics' staff within their busy work schedule. All treatment decisions regarding routine care of the patients remained at the discretion of the individual's primary care physician, enhancing their cooperation, and potentially resulting in better external validity. A designated database provided an interactive framework, which enabled a single coordination center to manage the study and create reliable documentation of clinical data and events. Eventually, within one year from study initiation, 3054 individuals were recruited for the study. The authors succeeded in retrieving reliable and significant clinical data, while relying on the organizational properties allowing for the centralized follow-up. This large scale clinical trial was conducted with very little resources, in a real life setting apparently providing extensive external validity.