The definitive evaluation of treatment to prevent a chronic disease with low incidence in middle age, such as cancer or cardiovascular disease, requires a trial with a large sample size of perhaps 20,000 or more. To help decide whether to implement a large true endpoint trial, investigators first typically estimate the effect of treatment on a surrogate endpoint in a trial with a greatly reduced ... [Show full abstract] sample size of perhaps 200 subjects. If investigators reject the null hypothesis of no treatment effect in the surrogate endpoint trial they implicitly assume they would likely correctly reject the null hypothesis of no treatment effect for the true endpoint. Surrogate endpoint trials are generally designed with adequate power to detect an effect of treatment on surrogate endpoint. However, we show that a small surrogate endpoint trial is more likely than a large surrogate endpoint trial to give a misleading conclusion about the beneficial effect of treatment on true endpoint, which can lead to a faulty (and costly) decision about implementing a large true endpoint prevention trial. If a small surrogate endpoint trial rejects the null hypothesis of no treatment effect, an intermediate-sized surrogate endpoint trial could be a useful next step in the decision-making process for launching a large true endpoint prevention trial.