After one or more Phase 2 trials show that a candidate preventive vaccine induces immune responses that putatively protect against an infectious disease for which there is no licensed vaccine, the next step is to evaluate the efficacy of the candidate. The trial-designer faces the question of what is the optimal size of the initial efficacy trial? Part of the answer will entail deciding between a large Phase 3 licensure trial or an intermediate-sized Phase 2b screening trial, the latter of which may be designed to directly contribute to the evidence-base for licensing the candidate, or, to test a scientific concept for moving the vaccine field forward, acknowledging that the particular candidate will never be licensable. Using the HIV vaccine field as a case study, we describe distinguishing marks of Phase 2b and Phase 3 prevention efficacy trials, and compare the expected utility of these trial types using Pascal's decision-theoretic framework. By integrating values/utilities on (1) correct or incorrect conclusions resulting from the trial; (2) timeliness of obtaining the trial results; (3) precision for estimating the intervention effect; and (4) resources expended; this decision framework provides a more complete approach to selecting the optimal efficacy trial size than a traditional approach that is based primarily on power calculations. Our objective is to help inform the decision-process for planning an initial efficacy trial design. Copyright © 2010 John Wiley & Sons, Ltd.