It is well established that a substantial and persistent placebo response occurs during randomized placebo-controlled trials in patients with irritable bowel syndrome (IBS.) Previously published attempts at characterizing placebo response and identifying any associated prognostic factors have generally consisted of meta-analyses of published summary data. In this work, a population model was developed to describe patient-level placebo response data from four Phase II and III clinical IBS trials (n = 965). The efficacy endpoint used in this analysis was whether or not each subject reported adequate relief from his/her IBS symptoms at each study week. The final model successfully described the placebo response time course and incorporated a number of covariates that had a significant influence on placebo response including duration of symptoms at baseline, gender, baseline pain severity and race. Once the model had been sufficiently validated, it was utilized to simulate proof of concept trials of a hypothetical IBS drug, which was assumed to increase an average patient’s day-to-day probability of adequate relief by 15%. Based on these simulations, a number of trial designs and features were evaluated including parallel, parallel with a placebo run-in, crossover, and randomized withdrawal. Of these, both the randomized withdrawal and crossover designed required substantially smaller sample sizes than the traditional parallel design in order to guarantee equivalent probabilities of trial success.