Polycystic ovary syndrome (PCOS) affects approximately 5% of the female population, and is a leading cause of infertility, primarily secondary to anovulation. Clomiphene citrate has been standard therapy for ovulation induction in patients seeking pregnancy, but recent evidence suggests that insulin sensitizing agents such as metformin may also be effective. The National Institute of Child Health and Human Development's Reproductive Medicine Network has begun a randomized, double-blind trial of clomiphene vs. metformin vs. clomiphene plus metformin for the induction of ovulation in patients with PCOS seeking pregnancy, with live birth rate as the primary outcome. Because the available literature was largely limited to surrogate outcomes such as ovulation and pregnancy rates, we created a Markov model to derive estimates of likely live birth rates in each arm. Using these estimates, we then constructed an algorithm that allowed only two formal comparisons between the three arms. First, we assumed that combination therapy would have to be superior to the next best single-agent therapy in order to be preferred, because of complexity, costs, increased side effects, etc. If combination therapy is not superior to the next best single agent, then the only other comparison of interest is between the two single agent therapies. Because the third possible comparison, between the best and worst of the three therapies, is not clinically relevant, it can be eliminated from formal statistical consideration, with subsequent reduction in sample size. Based on the opinion of the Network Steering Committee that a 15% absolute difference in live birth rates would be clinically relevant, our methodology resulted in a sample size of 226 per arm, or a total of 678 subjects. The PPCOS trial should definitively answer the question of the relative efficacy of metformin, clomiphene, and combination therapy in the treatment of infertile women with PCOS.