The Expanded Program on Immunization (EPI) has led to large reductions in morbidity and mortality among children in low-income countries. However, the basic EPI schedule may no longer be optimal because of changes in vaccines, programs, and epidemiologic circumstances. In addition, evidence has accumulated that some EPI vaccines may have nonspecific effects that increase or decrease mortality from subsequent infections with other unrelated organisms. There is therefore a need for randomized trials to evaluate the effects of alternative EPI schedules on all-cause mortality, as well as vaccine efficacy against the target diseases. We have reviewed the available literature on the nonspecific effects of vaccines on mortality, and compiled a list of potential trials that might address this issue. We have then ranked the trials based on the potential importance of the results and the ethical and practical considerations. Trials of early BCG vaccination in low-birth-weight babies, early measles vaccination, and altered timing of DTP vaccination all have a high priority.