BACKGROUND: Maternal mortality rates in India are estimated at 560/100,000 live births and postpartum hemorrhage (PPH) accounts for 35-56% of these deaths. Given that 50% of births in rural India occur at home, oral Misoprostol administered by minimally trained midwives may be an effective uterotonic agent for preventing PPH when the use of other uterotonics is not feasible. While the import for testing the effectiveness of this intervention may be readily obvious, the elements essential for the conduct of a scientific study in rural areas served by indigenous health workers may not be as evident. METHODS: We present the design as well as the preparation and development of an ongoing NICHD sponsored U.S.-Indian collaborative randomized, placebo-controlled, clinical trial (RCT) conducted in four Primary Health Center areas of Belgaum District, Karnataka, India. The primary goal of the trial is to assess the effectiveness of Misoprostol 600 microg orally in reducing the incidence of acute PPH (> or = 500 mL) in women delivering at home or in neighboring sub-centers. 1600 pregnant women will be randomized to receive Misoprostol or placebo immediately post-delivery of the infant. However, beyond testing the scientific merit of the RCT, this study also tests the feasibility of having indigenous midwives regularly using Misoprostol in rural areas as well as the willingness of these communities to accept this intervention. In addition, this paper also explores the international and community collaborations necessary for the conduct of this study. FINDINGS: It is necessary to have several critical elements in place, including international collaboration between the Indian and US research sites, funding through a private/public collaboration and trained scientists, as well as commitment from the community for the successful conduct of such a study. In the development and implementation of a RCT, careful attention must be paid to the training of field personnel involved in the delivery process and developing a data collection and monitoring system to ensure that information gathered is valid. CONCLUSIONS: A joint U.S.-Indian collaboration to test the efficacy and the feasibility of an innovative method to reduce PPH can serve as collaborative model to develop additional interventions to improve maternal mortality and morbidity. If Misoprostol is shown to be sufficiently safe and efficacious in the prevention of PPH, the appropriate government agencies will be encouraged to make the drug available to midwives (ANMs) and rurally located physicians for whom parenteral medications are either not permitted or impractical and/or unavailable. Such a project can serve as a model applicable to rural settings throughout the developing world for improving delivery practices and reducing maternal mortality and morbidity. These are important public health concerns in India and other developing nations.