Cardiovascular diseases account for almost half of all deaths from noncommunicable diseases, and almost 80% of these deaths occur in low- and middle-income countries such as India. The PrePAre (Primary pREvention strategies at the community level to Promote treatment Adherence to pREvent cardiovascular disease) trial was a primary prevention trial of community health workers aimed at improving adherence to prescribed pharmacological and nonpharmacological therapies in cardiovascular diseases. It was conducted at three geographically, culturally and linguistically diverse sites across India, comprising 28 villages and 5699 households. Planning and implementing large-scale community-based trials is filled with numerous challenges that must be tackled, while keeping in mind the local community dynamics. Some of the challenges are especially pronounced when the focus of the activities is on promoting health in communities where treating disease is considered a priority rather than maintaining health. This report examines the challenges that were encountered while performing the different phases of the trial, along with the solutions and strategies used to tackle those difficulties. We must strive to find feasible and cost-effective solutions to these challenges and thereby develop targeted strategies for primary prevention of cardiovascular diseases in resource-constrained rural settings.